Antimicrobial quinolones, their compositions and uses

ABSTRACT

This invention relates to novel antimicrobial compounds of formula;                    
     wherein X, R 1 , R 3 , R 5 , R 6 , and R 8  are defined in the claims, and to their optical isomers, diastereomers or enantiomers, as well as pharmaceutically-acceptable salts, hydrates, and biohydrolyzable esters, amides and imides thereof, and to compositions and uses of such compounds. The invention also relates to compounds derived from these compounds having antimicrobial uses.

CROSS REFERENCE

This application claims priority under Title 35, United States Code119(e) from Provisional Application Serial No. 60/058,891, filed Sep.15, 1997 and is a continuation-in-part of application Ser. No.09/139,859, filed Aug. 25, 1998 now abandoned.

FIELD OF THE INVENTION

The subject invention relates to novel antimicrobial compounds, theircompositions and their uses.

BACKGROUND

The chemical and medical literature describes compounds that are said tobe antimicrobial, i.e., capable of destroying or suppressing the growthor reproduction of microorganisms, such as bacteria. For example, suchantibacterials and other antimicrobials are described in Antibiotics,Chemotherapeutics, and Antibacterial Agents for Disease Control (M.Grayson, editor, 1982), and E. Gale et al., The Molecular Basis ofAntibiotic Action 2d edition (1981).

The mechanism of action of these antibacterials vary. However, they aregenerally believed to function in one or more of the following ways: byinhibiting cell wall synthesis or repair; by altering cell wallpermeability; by inhibiting protein synthesis; or by inhibitingsynthesis of nucleic acids. For example, beta-lactam antibacterials actthrough inhibiting the essential penicillin binding proteins (PBPs) inbacteria, which are responsible for cell wall synthesis. As anotherexample, quinolones act, at least in part, by inhibiting synthesis ofDNA, thus preventing the cell from replicating.

The pharmacological characteristics of antimicrobials, and theirsuitability for any given clinical use, vary. For example, the classesof antimicrobials (and members within a class) may vary in 1) theirrelative efficacy against different types of microorganisms, 2) theirsusceptibility to development of microbial resistance and 3) theirpharmacological characteristics, such as their bioavailability, andbiodistribution. Accordingly, selection of an appropriate antibacterial(or other antimicrobial) in a given clinical situation requires analysisof many factors, including the type of organism involved, the desiredmethod of administration, the location of the infection to be treatedand other considerations.

However, many such attempts to produce improved antimicrobials yieldequivocal results. Indeed, few antimicrobials are produced that aretruly clinically-acceptable in terms of their spectrum of antimicrobialactivity, avoidance of microbial resistance, and pharmacology. Thusthere is a continuing need for broad spectrum antimicrobials, which areeffective against resistant microbes.

Some 1,4-dihydroquinolone, naphthyridine or related heterocyclicmoieties are known in the art to have antimicrobial activity and aredescribed in the following references: R. Albrecht, Prog. Drug Research,Vol. 21, p. 9 (1977); J. Wolfson et al., “The Fluoroquinolones:Structures, Mechanisms of Action and Resistance, and Spectra of ActivityIn Vitro”, Antimicrob. Agents and Chemother., Vol. 28, p. 581 (1985); G.Klopman et al., Antimicrob. Agents and Chemother., Vol. 31, p. 1831(1987); M. P. Wentland et al., Ann. Rep. Med. Chem., Vol. 20, p. 145(1986); J. B. Cornett et al., Ann. Rep. Med. Chem., Vol. 21, p. 139(1986); P. B. Fernandes et al., Ann. Rep. Med. Chem., Vol. 22, p. 117(1987); A. Koga, et al., “Structure-Activity Relationships ofAntibacterial 6,7- and 7,8-Disubstituted1-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic Acids”, J. Med. Chem.,Vol. 23, pp. 1358-1363 (1980); J. M. Domagala et al., J. Med. Chem.,Vol. 31, p. 991 (1988); T. Rosen et al., J. Med. Chem., Vol. 31, p. 1586(1988); T. Rosen et al., J. Med. Chem., Vol. 31, p. 1598 (1988); B.Ledoussal et al., “Non 6-Fluoro Substituted Quinolone Antibacterials:Structure and Activity”, J. Med Chem., Vol. 35, p. 198-200 (1992); J. M.Domagala et al., “Quinolone Antibacterials Containing the New7-[3-(1-Aminoethyl)-1-pyrrolidinyl] Side Chain: The Effects of the1-Aminoethyl Moiety and Its Stereochemical Configurations on Potency andin Vivo Efficacy”, J. Med. Chem., Vol. 36, pp. 871-882 (1993); Hagen etal., “Synthesis and Antibacterial Activity of New Quinolones Containinga 7-[3-(1-Amino-1-methylethyl)-1-pyrrolidinyl] Moiety. Gram PositiveAgents with Excellent Oral Activity and Low Side-Effect Potential”, J.Med. Chem. Vol. 37, pp. 733-738 (1994); V. Ceechetti et al., “Studies on6-Aminoquinolines: Synthesis and Antibacterial Evaluation of6-Amino-8-methylquinolones”, J. Med. Chem., Vol. 39, pp. 436-445 (1996);V. Cecchetti et al., “Potent 6-Desfluoro-8-methylquinolones as New LeadCompounds in Antibacterial Chemotherapy”, J. Med. Chem., Vol. 39, pp.4952-4957 (1996); Hong et al., “Novel 5-Amino-6-methylquinoloneAntibacterials: a New Class of Non-6-fluoroquinolones”, Bioorg. of Med.Chem. Let., Vol. 7, pp. 1875-1878 (1997); U.S. Pat. No. 4,844,902 toGrohe on Jul. 4, 1989; U.S. Pat. No. 5,072,001 to Hagen & Suto on Dec.10, 1991; U.S. Pat. No. 5,328,908 to Demuth & White on Jul. 12, 1994;U.S. Pat. No. 5,457,104 to Bartel et al. on Oct. 10, 1995; U.S. Pat. No.5,556,979 to Philipps et al. on Sep. 17, 1996; European Patent Appl.572,259 of Ube Ind. pub. Dec. 1, 1993; European Patent Appl. 775,702 ofToyama Chem. Co. pub. May 28, 1997; Japanese Patent Pub. 62/255,482 ofKyorin Pharm. Co. pub. Mar. 1, 1995.

Structure activity relationships of the quinolones have been the subjectof detailed study for more than a decade. As a result of these studies,it has been determined by those in the art that certain structures, withspecific sites on the quinolone ring functionalized, have distinctadvantages over others. For example, A. Koga, et al.,“Structure-Activity Relationships of Antibacterial 6,7- and7,8-Disubstituted 1-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylicAcids”, J. Med. Chem, Vol. 23, pp. 1358-1363 (1980) (Koga) discloses thenon-equivalence of the 6-and 8-quinolonyl position, and the importanceof the substitution at the 6-quinolonyl position. Koga appears todemonstrate by examples that 6-fluoro, 8-hydrogen substitution issuperior to 6-hydrogen, 8-fluoro or halo. Perhaps as a result of thisearly structure activity work in this area, the art has focused on the6-fluorinated structures to provide the next generation of quinolones.Despite the work in this area, the full promise of the quinolones asantibacterials has not yet been exploited.

Examples of bacterial infections resistant to antibiotic therapy havebeen reported in the past; they are now a significant threat to publichealth in the developed world. The development of microbial resistance(perhaps as a result of the intense use of antibacterials over extendedperiods of time) is of increasing concern in medical science.“Resistance” can be defined as existence of organisms, within apopulation of a given microbial species, that are less susceptible tothe action of a given antimicrobial agent. This resistance is ofparticular concern in environments such as hospitals and nursing homes,where relatively high rates of infection and intense use ofantibacterials are common. See, e.g., W. Sanders, Jr. et al., “InducibleBeta-lactamases: Clinical and Epidemiologic Implications for Use ofNewer Cephalosporins”, Reviews of Infectious Diseases p. 830 (1988).

Pathogenic bacteria are known to acquire resistance via several distinctmechanisms including inactivation of the antibiotic by bacterial enzymes(e.g., b-lactamases hydrolyzing penicillin and cephalosporins); removalof the antibiotic using efflux pumps; modification of the target of theantibiotic via mutation and genetic recombination (e.g.,penicillin-resistance in Neiserria gonorrhoeae); and acquisition of areadily transferable gene from an external source to create a resistanttarget (e.g., methicillin-resistance in Staphylococcus aureus). Thereare certain Gram positive pathogens, such as vancomycin-resistantEnterococcus faecium, which are resistant to virtually all commerciallyavailable antibiotics.

Hence existing antibacterials have limited capacity in overcoming thethreat of resistance. Thus it would be advantageous to provide aquinolone with useful properties that can be used commercially againstresistant microbes.

OBJECTS OF THE INVENTION

It is an object of the subject invention to provide quinolone andquinolonyl antimicrobial compounds that are useful against a broadspectrum of microbes, and especially against bacteria.

It is a further object of the invention to provide such antimicrobialswhich are effective against quinolone-resistant microbes.

SUMMARY OF THE INVENTION

We have found a novel series of quinolone and quinolonyl compounds thatare effective against resistant microbes, and provide significantactivity advantages over the art. Furthermore, we have found that thesequinolone and quinolonyl compounds defy the art acceptedstructure/activity relationships.

The invention relates to compounds of formula

wherein:

(a) X is selected from

(b) R1 is selected from C₃ to about C₅ cycloalkyl, C₁ to about C₂alkanyl, C₂ to about C₃ linear alkenyl, C₃ to about C₄ branched alkanylor alkenyl, all such alkyl or cycloalkyl moieties being unsubstituted orsubstituted with from 1 to about 3 fluoro; and phenyl, unsubstituted orsubstituted with from 1 to about 3 fluoro, or with one hydroxy in the4-position;

(c) R3 is hydrogen or hydroxy;

(d) R5 is selected from hydrogen, hydroxy, amino, halo, C₁ to about C₂alkanyl, C₂ alkenyl, and methoxy, all alkyl moieties being unsubstitutedor substituted with from 1 to about 3 fluoro;

(e) R6 is selected from hydrogen, hydroxy, aminocarbonyl, bromo, cyano,C₁ to about C₂ alkanyl, C₂ to about C₄ alkenyl or alkynyl, all suchalkyl moieties being unsubstituted or substituted with from 1 to about 3fluoro, or such methyl or ethyl moieties being optionally substitutedwith one hydroxy or one amino;

(f) R8 is selected from chloro, bromo, methoxy, C₁ to about C₂ alkanyl,C₂ to about C₄ alkenyl, all such alkyl moieties being unsubstituted orsubstituted with from 1 to about 3 fluoro;

(g) R7 is amino which is attached to a ring carbon of X which is notadjacent to the ring nitrogen, the amino being unsubstituted orsubstituted with one or two C₁ to about C₃ alkanyl; or aminoalkanylwhich is attached to any ring carbon of X and is C₁ to about C₃ alkanylsubstituted with one amino, the amino being unsubstituted or substitutedwith one or two C₁ to about C₃ alkanyl; and

(h) each R9 is independently selected from hydrogen, C₁ to about C₄alkanyl, C₂ to about C₆ alkenyl or alkynyl, and a C₃ to about C₆ fusedor spirocycle alkyl ring; one R9 is optionally selected from hydroxy, C₁to about C₄ alkoxy, aryl, and heteroaryl; all alkyl and aryl portions ofR9 moieties being unsubstituted or substituted with one hydroxy or withfrom 1 to about 3 fluoro;

(j) a R7 moiety described in (g) and a R9 moiety described in (h) mayoptionally be connected thus forming a fused or spirocycle ring with theN-containing ring shown in (a), the fused or spirocycle ring comprisingfrom 2 to about 5 ring carbons and 0 or 1 ring nitrogen, but if suchrings are fused, R8 is preferably other than chloro or bromo or alkyl;

or an optical isomer, diastereomer or enantiomer thereof; apharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester,amide or imide thereof. In addition, compounds incorporating thecompounds of the invention, or using compounds of the invention asstarting materials are also contemplated in this invention.

It has been found that the compounds of this invention, and compositionscontaining these compounds, are effective antimicrobial agents against abroad range of pathogenic microorganisms with advantages in lowsusceptibility to microbial resistance, reduced toxicity, and improvedpharmacology.

DESCRIPTION OF THE INVENTION

The present invention encompasses certain compounds, dosage forms, andmethods of administering the compounds to a human or other animalsubject. Specific compounds and compositions to be used in the inventionmust, accordingly, be pharmaceutically acceptable. As used herein, sucha “pharmaceutically-acceptable” component is one that is suitable foruse with humans and/or animals without undue adverse side effects (suchas toxicity, irritation, and allergic response) commensurate with areasonable benefit/risk ratio.

Glossary of Terms

Unless otherwise specified, the following terms have the indicatedmeanings when used in this application.

“Alkanyl” is an unsubstituted or substituted, linear or branched,saturated hydrocarbon chain radical having from 1 to 8 carbon atoms,preferably from 1 to 4 carbon atoms. Preferred alkanyl groups include(for example) methyl, ethyl, propyl, isopropyl, and butyl.

“Alkenyl” is an unsubstituted or substituted, linear or branched,hydrocarbon chain radical having from 2 to 8 carbon atoms, preferablyfrom 2 to 4 carbon atoms, and having at least, preferably only one, onecarbon-carbon double bond.

“Alkynyl” is an unsubstituted or substituted, linear or branched,hydrocarbon chain radical having from 2 to 8 carbon atoms, preferablyfrom 2 to 4 carbon atoms, and having at least, preferably only one, onecarbon-carbon triple bond.

“Alkyl” includes alkanyl, alkenyl, and alkynyl as defined above, unlessspecifically limited otherwise to only one or two of them or by otherrestrictions. Alkyl retains this meaning when it is used as part ofanother word; examples are provided below (e.g., alkylene, haloalkyl).In such words, alkyl can be replaced by any of alkanyl, alkenyl, oralkynyl to narrow the meaning of such words accordingly.

“Alkylene” is a hydrocarbon diradical. Preferred alkylene includesethylene and methylene.

“Amino” is an unsubstituted or substituted —NH₂.

“Haloalkyl” is an alkyl with one or more halogens (fluoro, chloro,bromo, iodo) on the alkyl. Hence, fluoroalkyl is an example of asubgenus of haloalkyl.

“Heteroatom” is a nitrogen, sulfur or oxygen atom. Groups containing oneor more heteroatoms may contain different heteroatoms.

“Heteroalkyl” is an unsubstituted or substituted chain radical havingfrom 2 to 8 members comprising carbon atoms and at least one heteroatom.

“Carbocyclic ring” is an unsubstituted or substituted, saturated,unsaturated or aromatic, hydrocarbon ring radical. Carbocyclic rings aremonocyclic or are fused, bridged or spiro polycyclic ring systems.Monocyclic rings contain from 3 to 9 carbon atoms, preferably 3 to 6carbon atoms. Polycyclic rings contain from 7 to 17 carbon atoms,preferably from 7 to 13 carbon atoms.

“Cycloalkyl” is a saturated or unsaturated, but not aromatic,carbocyclic ring radical. Preferred cycloalkyl groups are saturated, andinclude cyclopropyl, cyclobutyl and cyclopentyl, especially cyclopropyl.

“Heterocyclic ring” is an unsubstituted or substituted, saturated,unsaturated or aromatic ring radical comprised of carbon atoms and oneor more heteroatoms in the ring. Heterocyclic rings are monocyclic orare fused, bridged or spiro polycyclic ring systems. Monocyclic ringscontain from 3 to 9 carbon and heteroatoms, preferably 3 to 6 carbon andheteroatoms. Polycyclic rings contain from 7 to 17 carbon andheteroatoms, preferably from 7 to 13 carbon and heteroatoms.

“Aryl” is an unsubstituted or substituted aromatic carbocyclic ringradical. Preferred aryl groups include (for example) phenyl,2,4-difluorophenyl, 4-hydroxyphenyl, tolyl, xylyl, cumenyl and naphthyl;more preferred is phenyl. Preferred substituents for aryl include fluoroand hydroxy.

“Heteroaryl” is an unsubstituted or substituted aromatic heterocyclicring radical. Preferred heteroaryl groups include (for example) thienyl,furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, quinolinyl,pyrimidinyl and tetrazolyl.

“Alkoxy” is an oxygen radical having a hydrocarbon chain substituent,where the hydrocarbon chain is an alkyl (i.e., —O-alkyl or —O-alkanyl).Preferred alkoxy groups are saturated, and include (for example)methoxy, ethoxy, propoxy and allyloxy.

“Alkylamino” is an amino radical having one or two alkyl substituents(e.g., —NH-alkyl). The alkyl groups are preferably saturated, andinclude (for example) methyl and ethyl.

“Arylalkyl” is an alkyl radical substituted with an aryl group.Preferred arylalkyl groups include benzyl and phenylethyl.

“Arylamino” is an amino radical substituted with an aryl group (e.g.,—NH-phenyl).

“Aryloxy” is an oxygen radical having a aryl substituent (e.g.,—O-phenyl).

“Acyl” or “carbonyl” is a radical formed by removal of the hydroxy froma carboxylic acid (e.g., R—C(O)—). Preferred groups include (forexample) formyl, and alkylacyl moieties such as acetyl and propionyl.

“Acyloxy” is an oxygen radical having an acyl substituent (i.e.,—O-acyl); for example, —O—C(O)-alkyl.

“Acylamino” is an amino radical having an acyl substituent (e.g.,—NH-acyl); for example, —NH—C(O)-alkyl.

“Halo”, “halogen”, or “halide” is a chloro, bromo, fluoro or iodoradical.

Also, as referred to herein, a “lower” hydrocarbon moiety (e.g., “lower”alkyl) is a hydrocarbon chain comprised of 1 to 4, preferably from 1 to2, carbon atoms.

A “pharmaceutically-acceptable salt” is a cationic salt formed at anyacidic (e.g., carboxyl) group, or an anionic salt formed at any basic(e.g., amino, alkylamino, dialkylamino, morphylino, and the like) groupon the compound of the invention. Since many of the compounds of theinvention are zwitterionic, either salt is possible and acceptable. Manysuch salts are known in the art. Preferred cationic salts include thealkali metal salts (such as sodium and potassium), alkaline earth metalsalts (such as magnesium and calcium) and organic salts, such asammonio. Preferred anionic salts include halides, sulfonates,carboxylates, phosphates, and the like. Clearly contemplated in suchsalts are addition salts that may provide an optical center, where oncethere was none. For example, a chiral tartrate salt may be prepared fromthe compounds of the invention, and this definition includes such chiralsalts. Salts contemplated are nontoxic in the amounts administered tothe patient-animal, mammal or human.

The compounds of the invention are sufficiently basic to formacid-addition salts. The compounds are useful both in the free base formand the form of acid-addition salts, and both forms are within thepurview of the invention. The acid-addition salts are in some cases amore convenient form for use. In practice, the use of the salt forminherently amounts to the use of the base form of the active. Acids usedto prepare acid-addition salts include preferably those which produce,when combined with the free base, medicinally acceptable salts. Thesesalts have anions that are relatively innocuous to the animal organism,such as a mammal, in medicinal doses of the salts so that the beneficialproperty inherent in the free base are not vitiated by any side effectsascribable to the acid's anions.

Examples of appropriate acid-addition salts include, but are not limitedto hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate,acetate, trifluoroacetate, nitrate, citrate, fumarate, formate,stearate, succinate, maleate, malonate, adipate, glutarate, lactate,propionate, butyrate, tartrate, methanesulfonate,trifluoromethanesulfonate, p-toluenesulfonate, dodecyl sulfate,cyclohexanesulfamate, and the like. However, other appropriatemedicinally acceptable salts within the scope of the invention are thosederived from other mineral acids and organic acids. The acid-additionsalts of the basic compounds are prepared by several methods. Forexample, the free base can be dissolved in an aqueous alcohol solutioncontaining the appropriate acid and the salt is isolated by evaporationof the solution. Alternatively, they may be prepared by reacting thefree base with an acid in an organic solvent so that the salt separatesdirectly. Where separation of the salt is difficult, it can beprecipitated with a second organic solvent, or can be obtained byconcentration of the solution.

Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention. All acid-addition salts are useful as sources of the freebase form, even if the particular salt per se is desired only as anintermediate product. For example, when the salt is formed only forpurposes of purification or identification, or when it is used as anintermediate in preparing a medicinally acceptable salt by ion exchangeprocedures, these salts are clearly contemplated to be a part of thisinvention.

“Host” is a substrate capable of sustaining a microbe, preferably it isa living organism, more preferably an animal, more preferably a mammal,more preferably still a human.

“Biohydrolyzable amides” are aminoacyl, acylamino, or other amides ofthe compounds of the invention, where the amide does not essentiallyinterfere, preferably does not interfere, with the activity of thecompound, or where the amide is readily converted in vivo by a host toyield an active compound.

“Biohydrolyzable imides” are imides of compounds of the invention, wherethe imide does not essentially interfere, preferably does not interfere,with the activity of the compound, or where the imide is readilyconverted in vivo by a host to yield an active compound. Preferredimides are hydroxyimides.

“Biohydrolyzable esters” are esters of compounds of the invention, wherethe ester does not essentially interfere, preferably does not interfere,with the antimicrobial activity of the compound, or where the ester isreadily converted in a host to yield an active compound. Many suchesters are known in the art, as described in U.S. Pat. No. 4,783,443,issued to Johnston and Mobashery on Nov. 8, 1988 (incorporated byreference herein). Such esters include lower alkyl esters, loweracyloxy-alkyl esters (such as acetoxymethyl, acetoxyethyl,aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters),lactonyl esters (such as phthalidyl and thiophthalidyl esters), loweralkoxyacyloxyalkyl esters (such as methoxycarbonyloxymethyl,ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters),alkoxyalkyl esters, choline esters and alkylacylaminoalkyl esters (suchas acetamidomethyl esters).

The illustration of specific protected forms and other derivatives ofthe Formula 1 compounds is not intended to be limiting. The applicationof other useful protecting groups, salt forms, etc. is within theability of the skilled artisan.

“Optical isomer”, “stereoisomer”, “diastereomer” as referred to hereinhave the standard art recognized meanings (Cf., Hawley's CondensedChemical Dictionary, 11th Ed.).

The compounds of the invention may have one or more chiral centers. As aresult, one may selectively prepare one optical isomer, includingdiastereomer and enantiomer, over another, for example by use of chiralstarting materials, catalysts or solvents, one may prepare bothstereoisomers or both optical isomers, including diastereomers andenantiomers at once (a racemic mixture). Since the compounds of theinvention may exist as racemic mixtures, mixtures of optical isomers,including diastereomers and enantiomers, or stereoisomers, they may beseparated using known methods, such as chiral resolution, chiralchromatography and the like.

In addition, it is recognized that one optical isomer, includingdiastereomer and enantiomer, or stereoisomer may have favorableproperties over the other. Thus when disclosing and claiming theinvention, when one racemic mixture is disclosed, it is clearlycontemplated that both optical isomers, including diastereomers andenantiomers, or stereoisomers substantially free of the other aredisclosed and claimed as well.

As used herein, a quinolone derivative includes prodrugs of a quinolone,or an active drug made from a quinolone. Preferably, such derivativesinclude lactams (e.g., cephems, carbacephems, penems, monolactams, etc.)covalently linked to the quinolone optionally via a spacer. Suchderivatives and methods to make and use them are apparent to the skilledartisan, given the teaching of this specification.

COMPOUNDS OF THE INVENTION

In Formula 1, X is selected from

Preferred X include the pyrrolidinyl ring above or the piperidinyl ringabove or the azetidinyl ring above; more preferred is the pyrrolidinylring; also more preferred is the piperidinyl ring.

In Formula 1, R1 includes certain alkyl, cycloalkyl, and aryl moieties.R1 cycloalkyl moieties include from about 3 to about 5 carbon atoms inthe ring, preferably 3 carbon atoms in the ring. R1 cycloalkyl moietiesare preferably saturated or unsaturated with one double bond; morepreferably R1 cycloalkyl are saturated (cycloalkanyl). R1 linear alkanylcontain from 1 to about 2 carbon atoms; methyl and ethyl are preferred,especially ethyl. R1 linear alkenyl contain from 2 to about 3 carbonatoms; ethenyl is preferred. R1 branched alkanyl and alkenyl containfrom 3 to about 4 carbon atoms; branched alkanyl are preferred;isopropyl, isopropenyl, isobutyl, isobutenyl, and t-butyl are alsopreferred. All of the foregoing alkyl (alkanyl, alkenyl, and alkynyl) orcycloalkyl moieties aforementioned in this paragraph are unsubstitutedor substituted with from 1 to about 3 fluoro moieties. R1 aryl moietiesinclude phenyl, unsubstituted or substituted with from 1 to about 3fluoro, or with one hydroxy in the 4-position; substituted phenyl arepreferred. Preferred R1 is selected from cyclopropyl, ethyl, phenylsubstituted with 1 to 3 fluoro, and 4-hydroxyphenyl; more preferred is2,4-difluorophenyl, and especially cyclopropyl or ethyl.

In Formula 1, R3 is hydrogen or hydroxy; preferably R3 is hydroxy. WhenR3 is hydroxy, it and the carbonyl to which it is attached are acarboxylic acid moiety. As such, it is a potential point of formationfor the subject compounds of pharmaceutically-acceptable salts, andbiohydrolizable esters, aminoacyls, and amides, as described herein.Compounds having any such variations at the R3 position are included inthe subject invention.

In Formula 1, R5 includes hydrogen, amino, halo, hydroxy, methoxy, andcertain alkyl. R5 alkanyl moieties have from 1 to about 2 carbon atoms,preferably 1 carbon atom. R5 alkenyl moieties preferably have 2 carbonatoms. All R5 alkyl and methoxy moieties are unsubstituted orsubstituted with from 1 to about 3 fluoro moieties. Preferred R5 isselected from hydrogen, hydroxy, chloro, bromo, amino, methyl,monofluoromethyl, difluoromethyl, and trifluoromethyl. More preferred R5is selected from hydrogen, hydroxy, amino, and methyl, especiallyhydrogen.

In Formula 1, R6 includes hydrogen, hydroxy, aminocarbonyl, bromo,cyano, and certain alkyl. R6 alkanyl moieties have from 1 to about 2carbon atoms; preferred are methyl and ethyl; more preferred is methyl.R6 alkenyl and alkynyl moieties have from 2 to about 4 carbon atoms,preferably 2 carbon atoms, with one double or triple, preferably double,bond; ethenyl is preferred. All R6 alkyl moieties are unsubstituted orsubstituted with from 1 to about 3 fluoro. R6 methyl or ethyl moietiesare optionally substituted with one hydroxy moiety or one amino moiety.Preferred R6 is selected from hydrogen, hydroxy, methyl,monofluoromethyl, difluoromethyl, and trifluoromethyl. More preferred R6is hydrogen.

In Formula 1, R8 includes chloro, bromo, methoxy, methylthio, andcertain alkyl. R8 alkanyl moieties have from 1 to about 2 carbon atoms;methyl is preferred. R8 alkenyl moieties have from 2 to about 4 carbonatoms; ethenyl is preferred. All R8 alkyl moieties are unsubstituted orsubstituted with from 1 to about 3 fluoro moieties. Preferred R8 isselected from chloro, methyl, methoxy, methylthio, monofluoromethyl,difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, andtrifluoromethoxy. More preferred R8 is selected from methyl substitutedwith from 1 to 3 fluoro, methoxy, methylthio, and chloro; especiallyeither methoxy or methylthio or chloro.

In X of Formula 1, R7 includes amino which is attached to a ring carbonwhich is not adjacent to the ring nitrogen. Such R7 amino isunsubstituted or substituted with one or two alkanyl having from 1 toabout 3 carbon atoms, preferably methyl or ethyl, more preferablymethyl; preferred amino R7 is unsubstituted or substituted with one suchalkanyl moiety. When X comprises the piperidinyl ring, R7 is preferablyan unsubstituted or substituted amino moiety, preferably attached at the3-position or 4-position of the piperidinyl ring, more preferably at the3-position. More preferred R7, especially when X comprises thepiperidinyl ring, is amino or methylamino.

R7 also includes aminoalkanyl, the alkanyl having from 1 to about 3carbon atoms, preferably methyl, ethyl, or isopropyl, the alkanyl beingsubstituted with one amino, such amino being unsubstituted orsubstituted with 1 or 2, preferably 1, alkanyl having from 1 to about 3carbon atoms, preferably ethyl or especially methyl. Such aminoalkanylcan be attached to any carbon of the ring of X; preferably it isattached to a carbon not adjacent to the ring nitrogen. R7 is preferablysuch aminoalkanyl, especially if R8 is any unsubstituted alkyl, alsoparticularly if X comprises the pyrrolidinyl ring. Preferred R7,especially when X comprises the pyrrolidinyl ring, is selected fromaminomethyl, methylaminomethyl, 1-aminoethyl, 1-methylaminoethyl,1-amino-1-methylethyl, and 1-methylamino-1-methylethyl; such moietiesare preferably attached at the 3-position of the pyrrolidinyl ring.

The amino moiety of R7 is a potential point of formation for the subjectcompounds of a pharmaceutically-acceptable anionic salt; such salts areincluded in the subject invention compounds. Preferred salts are acidaddition salts with, for example, HCl, CH₃SO₃H, HCOOH, or CF₃COOH.

In X of Formula 1, R9 represents all the moieties other than R7 on thering carbons of the piperidinyl, pyrrolidinyl, and azetidinyl rings of Xshown above; such moieties include hydrogen, alkyl, aryl, heteroaryl,hydroxy, or alkoxy. Alkyl R9 may be mono- or disubstituents on each ringcarbon atom to which R7 is not attached or mono-substituents on the ringcarbon to which R7 is attached (i.e., each ring carbon of X may have twohydrogens, one hydrogen and R7, one hydrogen and one alkyl, one alkyland R7, or two alkyls bonded to it). Preferably no more than two ringcarbons have alkyl R9 substituents; more preferably only one ring carbonhas alkyl R9 substituents; also preferably all R9 are hydrogen. Anon-hydrogen, non-alkyl R9 (aryl, heteroaryl, hydroxy or alkoxy) mayoptionally be a mono-substituent on a ring carbon to which R7 is notattached. Preferably there is no more than one non-hydrogen, non-alkylR9 for a subject compound; more preferably there are none.

Non-hydrogen R9 includes linear, branched or cyclic alkanyl, preferablylinear or branched, more preferably linear, having from 1 to about 4carbon atoms; methyl and ethyl are preferred; methyl is more preferred.Non-hydrogen R9 includes linear, branched or cyclic alkenyl and alkynyl,preferably linear or branched, more preferably linear, having from 2 toabout 6 carbon atoms, preferably from 2 to about 4 carbon atoms; ethenylis preferred. Non-hydrogen R9 includes hydroxy and linear or branchedalkoxy having from 1 to about 4 carbon atoms, preferably methoxy orethoxy. Non-hydrogen R9 includes aryl, preferably phenyl; andheteroaryl, preferably having 5 or 6 ring atoms with one or two,preferably one, heteroatom that is preferably oxygen or sulfur, morepreferably thienyl or furyl.

Alkyl R9, especially dialkyl R9, are preferably attached to a carbon ofthe ring of X which is adjacent to the ring nitrogen, especially when Xcomprises the pyrrolidinyl ring. A non-hydrogen, non-alkyl R9 ispreferably attached to a carbon of the ring of X which is not adjacentto the ring nitrogen. Also preferred, when X comprises the piperidinylring and R7 is attached to the 3-carbon of the ring, is for onenon-hydrogen R9 to be attached to the 4-carbon of the ring.

Two alkyl R9 can be attached together thus forming a fused or aspirocycle alkyl ring with the N-containing ring of X, the fused orspirocycle ring having from about 3 to about 6 carbon atoms. Such fusedor spirocycle alkyl ring is preferably saturated or unsaturated with onedouble bond, more preferably saturated. A spirocyclopropyl ring isparticularly preferred.

All alkyl and aryl portions of R9 moieties are unsubstituted orsubstituted with one hydroxy moiety or with from 1 to about 3 fluoromoieties, preferably unsubstituted.

More preferred R9 is selected from hydrogen, methyl, dimethyl,spirocyclopropyl, and ethyl; more preferred are ethyl, dimethyl, andspirocyclopropyl; and especially hydrogen.

Optionally, an alkyl R9 can be connected to R7 thus forming a fused or aspirocycle ring with the N-containing ring of X, the fused or spirocyclering having from 2 to about 5 ring carbon atoms and 0 or 1 ring nitrogenatom (from R7). Such fused or spirocycle ring may be a hydrocarbon ringwith an amino or aminoalkyl substituent, the amino being from R7; or itmay be a heterocyclic ring with the R7 amino nitrogen being a ringnitrogen. Such ring may have one or two alkanyl substituents. Such fusedor spirocycle ring is preferably saturated or unsaturated with onedouble bond; more preferably it is saturated. If such ring is fused, R8is other than chloro, preferably other than chloro and bromo, alsopreferably other than alkyl, more preferably is methoxy or methylthio,especially methoxy.

Subject compounds having R7 or R9 spirocycles are named according to thefollowing numbering system: the numbering starts at the smaller ring,completing around the larger ring which forms a spiro junction, e.g., atcarbon 3 when the smaller ring is cyclopropyl as for the followingexample:

The aza nomenclature used herein follows the conventional nomenclatureand is the position where the ring nitrogen is attached to the quinolonenucleus.

As used herein, any radical is independently selected each time it isused (e.g., R1 and R5 need not be the same in all occurrences indefining a given compound of this invention).

The compounds of the invention may contain chiral center(s), thus anysuch compound includes and contemplates each optical isomer,diastereomer or enantiomer thereof, in purified or substantiallypurified form, and mixtures thereof, including racemic mixtures.

The following exemplary compounds are made using the proceduresdescribed herein and variations thereof which are within the purview ofthe skilled artisan's practice. The examples below do not limit theinvention, but rather serve to illustrate some of the embodiments of theinvention.

Preferred examples of the quinolones of the subject invention withstructures of Formula 2 are provided in the table below:

In the following examples, R₁ is cyclopropyl, R₃ is hydroxy, and zrepresents the preferred chirality of the R7 radical's attachment on thepyrrolidine ring, although other chirality is also envisioned. Incompounds where R7 is —CH(CH₃)NH₂, it is preferred that theconfiguration of this radical be R.

Example R5 R6 R7 R8 z 1 —NH₂ H —NH₂ Cl S 2 —NH₂ H —CH₂NH₂ Cl S 3 —NH₂ H—CH(CH₃)NH₂ Cl R 4 F H —NH₂ Cl S 5 F H —CH₂NH₂ Cl S 6 F H —CH(CH₃)NH₂ ClR 7 —OCH₃ H —NH₂ Cl S 8 H H —CH₂NH₂ CH₃ S 9 H H —CH(CH₃)NH₂ CH₃ R 10 —OHH —NH₂ Cl S 11 —OH H —CH₂NH₂ Cl S 12 —OH H —CH(CH₃)NH₂ Cl R 13 H H —NH₂Cl S 14 H H —CH₂NH₂ Cl S 15 H H —CH(CH₃)NH₂ Cl R 16 H H —NH₂ OCH₃ S 17 HH —CH₂NH₂ OCH₃ S 18 H H —CH(CH₃)NH₂ OCH₃ R 19 H Br —NH₂ Cl S 20 H Br—CH₂NH₂ Cl S 21 H Br —CH(CH₃)NH₂ Cl R 22 H —CH₃ —NH₂ Cl S 23 H —CH₃—CH₂NH₂ Cl S 24 H —CH₃ —CH(CH₃)NH₂ Cl R 25 H —CHCH₂ —NH₂ Cl S 26 H—CHCH₂ —CH₂NH₂ Cl S 27 H —CHCH₂ —CH(CH₃)NH₂ Cl R 28 H —OH —NH₂ Cl S 29 H—OH —CH₂NH₂ Cl S 30 H —OH —CH(CH₃)NH₂ Cl R 31 H -CN —NH₂ Cl S 32 H -CN—CH₂NH₂ Cl S 33 H -CN —CH(CH₃)NH₂ Cl R 34 H —CH₂OH —NH₂ Cl S 35 H —CH₂OH—CH₂NH₂ Cl S 36 H —CH₂OH —CH(CH₃)NH₂ Cl R 37 H —CH₂NH₂ —NH₂ Cl S 38 H—CH₂NH₂ —CH₂NH₂ Cl S 39 H —CH₂NH₂ —CH(CH₃)NH₂ Cl R 40 H —CONH₂ —NH₂ Cl S41 H —CONH₂ —CH₂NH₂ Cl S 42 H —CONH₂ —CH(CH₃)NH₂ Cl R 43 H H —C(CH₃)₂NH₂Cl R 44 H H —C(CH₃)₂NH₂ OCH₃ R 45 H H —CH(CH₃)NHCH₃ OCH₃ R 46 H H—C(CH₃)₂NHCH₃ OCH₃ R 47 H H —C(CH₃)₂NH₂ OCH₃ R 48 H H —C(CH₃)₂NH₂ Cl R49 H H —CH(CH₃)NHCH₃ Cl R 50 H H —C(CH₃)₂NHCH₃ Cl R 51 H H —CH(CH₃)NH₂SCH₃ R 52 H H —C(CH₃)₂NH₂ SCH₃ R 53 H H —CH₂NH₂ SCH₃ R 54 H H —NH₂ SCH₃S

Preferred examples of the quinolones of the subject invention withstructures of Formula 1 are provided in the table below.

In the following examples, R3 is hydroxy, R5 and R6 are both hydrogen,and z represents the preferred chirality, if any, of attachment of theR7 radical to the respective pyrrolidine or piperidine ring, althoughother chirality is also envisioned.

Example R8 R1* X* z 55 56 —OCH₃ —Cl

— — 57 58 —OCH₃ —Cl

— — 59 60 —OCH₃ —Cl

— — 61 62 —OCH₃ —Cl

— — 63 64 65 —OCH₃ —Cl —SCH₃

S S S 66 67 —OCH₃ —Cl

S S 68 69 —OCH₃ —Cl

— — 70 71 —OCH₃ —Cl

— — 72 73 —OCH₃ —Cl

S S 74 75 —OCH₃ —Cl

— — 76 77 —OCH₃ —Cl

S S 78 79 —OCH₃ —Cl

S S 80 81 —OCH₃ —Cl

— — 82 83 —OCH₃ —Cl

— — 84 85 86 —OCH₃ —Cl —SCH₃

R R R 87 88 —OCH₃ —Cl

R R 89 90 —OCH₃ —Cl

R R 91 92 —OCH₃ —Cl

R R 93 94 95 —OCH₃ —Cl —SCH₃ CH₃CH₂— CH₃CH₂— CH₃CH₂—

R R R 96 97 —OCH₃ —Cl CH₃CH₂— CH₃CH₂—

R R 98 99 —OCH₃ —Cl CH₃— CH₃—

R R 100  101  —OCH₃ —Cl

S S 102  103  —OCH₃ —Cl

S S 104  105  —OCH₃ —Cl

R R 106  107  —OCH₃ —Cl

R R 108  109  —OCH₃ —Cl CFH₂CH₂— CFH₂CH₂—

R R 110  111  —OCH₃ —Cl

R R *Each structure depicted in this column generally pertains to thetwo or three different Examples with which it is grouped.

In addition, it is recognized that for purification, administration andthe like, salts and other derivatives of the above compounds are oftenused. Thus, a pharmaceutically-acceptable salt, hydrate, orbiohydrolyzable ester, amide or imide thereof is contemplated as part ofthe subject invention.

The subject invention compounds above are also useful precursors forcompounds of formula Q-L-B, wherein Q is a compound of Formula 1, L is alinking moiety, and B is a lactam containing moiety. This formulaincludes optical isomers, disatereomers or enantiomers thereof;pharmaceutically-acceptable salts, hydrates, or biohydrolyzable esters,amides and imides thereof These compounds and their uses are disclosedin U.S. Pat. No. 5,180,719 issued Jan. 19, 1993; U.S. Pat. No. 5,387,748issued Feb. 7, 1995; U.S. Pat. No. 5,491,139 issued Feb. 13, 1996; U.S.Pat. No. 5,530,116 issued Jun. 25, 1996; and EPO publications 0366189published May 2, 1990 and 0366640 published May 2, 1990, allincorporated herein by reference. For compositions and methods of use,the compounds of formula Q-L-B are useful in the same way as compound ofFormula 1. Thus, they can be interchanged in the composition examplesherein.

Biological activities of the invention compounds can be compared tociprofloxacin and the other known antimicrobial quinolone compounds.Compounds of the subject invention provide better antibacterialproperties against certain quinolone resistant bacteria compared tociprofloxacin and certain other prior art compounds. When tested againstquinolone-resistant bacteria such as S. aureus, S. saprophyticus, E.faecalis, S. pyogenes, S. pneumoniae, S. viridans, E. coli, P.aeruginosa, P. mirabilis, K. pneumoniae, E. cloacae, certain compoundsof the subject invention have been found to have MIC values (μ/ml) thatare up to about 500 times lower than ciprofloxacin.

METHODS OF MAKING THE COMPOUNDS

In making the compounds of the invention, the order of synthetic stepsmay be varied to increase yield of desired product. In addition, theskilled artisan will also recognize the judicious choice of reactants,solvents, and temperatures is an important component in successfulsynthesis. While the determination of optimal conditions, etc. isroutine, it will be understood that a variety of compounds can begenerated in a similar fashion, using the guidance of the scheme below.

The starting materials used in preparing the compounds of the inventionare known, made by known methods, or are commercially available as astarting material.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out standard manipulations of organiccompounds without further direction; that is, it is well within thescope and practice of the skilled artisan to carry out suchmanipulations. These include, but are not limited to, reduction ofcarbonyl compounds to their corresponding alcohols, oxidations,acylations, aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification and saponification and the like.Examples of these manipulations are discussed in standard texts such asMarch, Advanced Organic Chemistry (Wiley), Carey and Sundberg, AdvancedOrganic Chemistry (Vol. 2), Fieser & Feiser, Reagents for OrganicSynthesis (16 volumes), L. Paquette, Encyclopedia of Reagents forOrganic Synthesis (8 volumes), Frost & Fleming, Comprehensive OrganicSynthesis (9 volumes) and the like.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionality is masked or protected in themolecule, thus avoiding any undesirable side reactions and/or increasingthe yield of the reaction. Often the skilled artisan utilizes protectinggroups to accomplish such increased yields or to avoid the undesiredreactions. These reactions are found in the literature and are also wellwithin the scope of the skilled artisan. Examples of many of thesemanipulations can be found for example in T. Greene, Protecting Groupsin Organic Synthesis. Of course, amino acids used as starting materialswith reactive side chains are preferably blocked to prevent undesiredside reactions.

General procedures for preparing quinolone moieties useful in making thecompounds of the subject invention are described in the followingreferences, all incorporated by reference herein (including articleslisted within these references); Progress in Drug Research, Vol. 21, pp.9-104 (1977); J. Med. Chem., Vol. 23, pp. 1358-1363 (1980); J. Med.Chem., Vol. 29, pp. 2363-2369 (1986); J. Med. Chem., Vol. 31, p. 503(1988); J. Med. Chem., Vol. 31, pp. 503-506 (1988); J. Med. Chem., Vol.31, pp. 983-991 (1988); J. Med. Chem., Vol. 31, pp. 991-1001 (1988); J.Med. Chem., Vol. 31, pp. 1586-1590 (1988); J. Med. Chem., Vol. 31, pp.1598-1611 (1988); J. Med. Chem., Vol. 32, pp. 537-542 (1989); J. Med.Chem., Vol. 32, p. 1313 (1989); J. Med. Chem., Vol. 32, pp. 1313-1318(1989); Drugs Exptl. Clin. Res., Vol. 14, pp. 379-383 (1988); J. Pharm.Sci., Vol. 78, pp. 585-588 (1989); J. Het. Chem., Vol. 24, pp. 181-185(1987); J. Het. Chem., Vol. 25, pp. 479-485 (1988); Chem. Pharm. Bull.,Vol. 35, pp. 2281-2285 (1987); Chem. Pharm. Bull., Vol. 36, pp.1223-1228 (1988); U.S. Pat. No. 4,594,347, Jun. 10, 1986; U.S. Pat. No.4,599,334, Jul. 8, 1986; U.S. Pat. No. 4,687,770, Aug. 1, 1987; U.S.Pat. No. 4,689,325, Aug. 25, 1987; U.S. Pat. No. 4,767,762, Aug. 30,1988; U.S. Pat. No. 4,771,055, Sep. 13, 1988; U.S. Pat. No. 4,795,751,Jan. 3, 1989; U.S. Pat. No. 4,822,801, Apr. 18, 1989; U.S. Pat. No.4,839,355, Jun. 13, 1989; U.S. Pat. No. 4,851,418, Jul. 25, 1989; U.S.Pat. No. 4,886,810, Dec. 12, 1989; U.S. Pat. No. 4,920,120, Apr. 241990; U.S. Pat. No. 4,923,879, May 8, 1990; U.S. Pat. No. 4,954,507,Sep. 4, 1990; U.S. Pat. No. 4,956,465, Sep. 11, 1990; U.S. Pat. No.4,977,154, Dec. 11, 1990; U.S. Pat. No. 4,980,470, Dec. 25, 1990; U.S.Pat. No. 5,013,841, May 7, 1991; U.S. Pat. No. 5,045,549, Sep. 3, 1991;U.S. Pat. No. 5,290,934, Mar. 1, 1994; U.S. Pat. No. 5,328,908, Jul. 12,1994; U.S. Pat. No. 5,430,152, Jul. 4, 1995; European Patent Publication172,651, Feb. 26, 1986; European Patent Publication 230,053, Jul. 29,1987; European Patent Publication 230,946, Aug. 5, 1987; European PatentPublication 247,464, Dec. 2, 1987; European Patent Publication 284,935,Oct. 5, 1988; European Patent Publication 309,789, Apr. 5, 1989;European Patent Publication 332,033, Sep. 13, 1989; European PatentPublication 342,649, Nov. 23, 1989; and Japanese Patent Publication09/67,304 (1997).

The compounds are generally made by methods which include thosedisclosed in the references above. A preferred method is to prepare thequinolone moiety with a suitable leaving group at the 7 position andhave that leaving group displaced by the heterocycle -X as a last step.Examples of these methods follow.

The quinolone compounds of the subject invention may be prepared severalways. Versatile methodologies for providing the compounds of theinvention are shown in Scheme I below:

In Scheme I, Y can be bromo, iodo, nitro, amino, acetyl, or likemoieties known to the skilled chemist; preferred Y is bromo or nitro.

Alternatively, the general methodology of Scheme II can be used to makecertain subject compounds.

A preferred process for preparing the benzoic acid precursors of SchemesI and II is described and exemplified herein below. These benzoic acidderivatives have the formula:

In this process, 2,4-difluoro-bromobenzene:

is treated with a strong, non-nucleophilic base. This base may be anybase useful in permutational hydrogen-metal exchange. Preferred basesinclude lithium diisopropylamide (LDA), lithium2,2,6,6-tetramethylpiperidide (LiTMP), lithium bis(trimethylsilyl)amide(LTSA), t-butoxide, or other known bases for this purpose. Suitablebases are known in the literature, and can be found in common referencetexts as non-nucleophilic bases. Most preferred is LDA, which producesintermediates that are reasonably stable over a range of times andtemperatures. It is preferred that the temperature of this reaction isfrom about −80° C. up to about 40° C., more preferably up to about roomtemperature, most preferably to about −40° C. Temperature may vary withthe base used, for example the most preferred reaction temperature isabout −65° C. with LDA. Reaction times may be up to about 24 hours,preferably about 2 hours, most preferably the process is carried on assoon as it is apparent that the resulting benzene derivative may proceedto the next step in the process. It is also preferred that this reactiontake place under an inert atmosphere.

After the base has reacted with the 1-bromo-2,4-fluorobenzene, anelectrophilic reagent provides the desired R8 substituent or afunctional group which can be transformed into the desired R8substituent, thus producing a compound of formula:

Solvents suitable for this reaction are typically aprotic. Preferablythese solvents are compatible with the bases used in the step above.More preferred solvents include the ethers and glymes, most preferablytetrahydrofuran (THF). Such solvents are known in the art, and suitablesubstitutions are made depending on the base, electrophile, and thepolarity and solubility characteristics of the reactants and resultingcompound.

This 3-R8-2,4-difluoro-bromobenzene compound is useful in making thecorresponding benzoic acid and related intermediates for the eventualsynthesis of the quinolone or quinolone derivatives of the subjectinvention. This benzoic acid is prepared by treating the aboveR8-benzene compound with an equivalent of a reagent useful inpermutational halogen-metal exchange. Preferred reagents includen-butyllithium, magnesium, lithium or other known reagents for thispurpose. Suitable reagents are known in the literature, and can be foundin common reference texts. The most preferred base is n-butyllithium,which produces intermediates that are reasonably stable over a range oftimes and temperatures. It is preferred that the temperature for thisreaction is at least −80° C. up to about 40° C., more preferably up toabout room temperature, most preferably to about −40° C. Temperature mayvary with the base used, for example the most preferred reactiontemperature is about −70° C. with n-butyllithium. Reaction times may beup to about 24 hours, preferably about 15 min, most preferably theprocess is carried on as soon as it is apparent that the resultingintermediate derivative may proceed to the next step in the process. Itis also preferred that this reaction take place in an inert atmosphere.

The intermediate resulting from the last reaction above is treated withcarbon dioxide or N,N-dimethylformamide (DMF), most preferably carbondioxide. Often these reactions are exothermic, so it is preferred thatthe temperature be maintained by cooling the reaction to prevent sidereactions, and the like. If carbon dioxide is used, the resultingbenzoic acid compound is useful without further purification after atypical work up:

If DMF or a similar formylating compound is used, the resultingbenzaldehyde compound is oxidized to the corresponding benzoic acid viaoxidation. This reaction may occur in the presence of air, or by usingany other known oxidizing reagents. The same resulting benzoic acidcompound is useful without further purification after a typical work up.

The benzoic acid compound prepared by the above method is amenable toderivatization of the R6 position as well. If derivatization of thisposition is desired, the reactions chosen depend on the desiredfunctionality, for example Halogenation:

Where Z is a halide, preferably bromine. This reaction occurs underacidic conditions, such as in acetic acid, preferably with a halideactivating reagent, such as a silver reagent (e.g., AgNO₃).

Nitration:

Nitration occurs via treatment with activated nitric acid, such as in amixture of nitric and sulfuric acids. Reduction of the nitro compound tothe corresponding amine may be performed via any appropriate reductionprocess.

Acylation:

Preparation of acyl compounds is accomplished by introducing anacylating reagent, for example R′COCl (where R′ is an alkyl or aryl),preferably in the presence of a Lewis acid, for example AlCl₃. Thecompound formed as a result is amenable to Baeyer-Villiger chemistry toprovide a R6 hydroxyl, that may optionally be etherified.

R5 may be derivatized using similar methodologies described for R6.

For illustration, the following examples of making the benzoic acidprecursors are provided; the examples are not meant to be limiting.

PRECURSOR EXAMPLE A

3-Chloro-2,4-difluoro-bromobenzene

To a solution of 19 ml (0.135 mole) of diisopropylamine in 125 ml oftetrahydrofuran (THF) cooled at −20° C. is added 80 ml of n-butyllithium(1.6 M in hexane). The temperature is raised to 0° C. for 5 minutes andlowered to −78° C. Then 25 g (0.129 mole) of 2,4-difluoro-bromobenzeneis then added and the reaction is stirred at −65° C. for 2 hours. Then,25 ml (0.164 mole) of hexachloroacetone is added and the solution iswarmed to room temperature. After evaporation of the solvent, theresidue is distilled under vacuum to give the desired product.

3-Chloro-2,4-difluorobenzoic acid

To a solution of 21.5 g (0.0945 mole) of3-chloro-2,4-difluoro-bromobenzene in 220 ml of ether at −78° C. isadded 59 ml of 1.6 M n-butyllithium diluted in 60 ml of ether keepingthe temperature below −70° C. After 15 minutes, CO₂ is bubbled in thereaction keeping the temperature below −70° C. After warming to roomtemperature, water and hydrochloric acid are added and the organic phaseis separated, and dried. Removal of the solvent affords the desiredproduct.

PRECURSOR EXAMPLE B

3-Methyl-2,4-difluoro-bromobenzene

Diisopropylamine (11.9 ml, 85 mmol) is dissolved in 50 ml of anhydrousTHF and cooled in a dry ice/acetone bath. n-Butyllithium (34 ml of a 2.5M solution in hexanes, 85 mmol) is added dropwise. After 15 minutes, asolution of 1-bromo-2,4-difluorobenzene (16 g, 83 mmol) in 8 ml of THFis added at a rate to keep the temperature below −65° C. The reaction isstirred for 2.5 hours then a solution of iodomethane (10.3 ml, 166 mmol)in 8 ml of THF is added to the reaction. The ice bath is removed and thereaction is allowed to warm to room temperature. After 2 hours thereaction is quenched with water and 1N HCl. The aqueous layer isextracted twice with ether. The combined organics are washed with brineand dried over Na₂SO₄. Removal of the solvent affords the desiredproduct.

3-Methyl-2,4-difluorobenzoic acid

3-Methyl-2,4-difluoro-bromobenzene (16.07 g 77.6 mmol) is dissolved in120 ml anhydrous ether and cooled in a dry ice/acetone bath. A solutionof butyllithium (20.5 ml of a 2.5 M solution in hexanes, 76.2 mmol) in15 ml of ether is added dropwise at a rate to keep the temperature below−65° C. After 45 minutes, CO₂ is bubbled through the solution keepingthe temperature below −65° C. After the temperature stabilized, CO₂bubbling is continued as the reaction is allowed to warm to roomtemperature. The mixture is quenched with 30 ml of water and acidifiedto pH 2 with 1N HCl. The layers are separated and the aqueous layer isextracted with ether. The combined organics are washed with brine andsaturated sodium bicarbonate. The bicarbonate layer is then acidifiedwith 1N HCl to pH 3. The resulting solid is filtered, washed with water,and dried under vacuum.

PRECURSOR EXAMPLE C

3-Hydroxy-2,4-difluoro-bromobenzene

A quantity of 40.2 ml of 2.0 M lithium diisopropylamine (LDA) isdissolved in 80 ml of THF at −78° C. and 15.4 g of2,4-difluorobromobenzene is added keeping the temperature below −65° C.The reaction is stirred at −65° C. for 2 hours and 6.6 ml of 6 Manhydrous t-butyl hydroperoxide is added. After warming to roomtemperature, 100 ml of water is added and the mixture acidified. Thesolvent is removed by evaporation and the aqueous layer extracted withether. The extracts are dried and then concentrated to give the desiredproduct.

3-Methoxy-2,4-difluoro-bromobenzene

A quantity of 3.7 g of 3-hydroxy-2,4-difluoro-bromobenzene is dissolvedin 25 ml of acetone and 2.5 g of potassium carbonate is added followedby 2.2 ml of methyl iodide. The mixture is stirred at 20° C. for 6 hoursand the solvent evaporated. After addition of dichloromethane, thesuspension is filtered. Evaporation of the solvent affords the desiredproduct.

3-Methoxy-2,4-difluorobenzoic acid

A procedure analogous to the 3-chloro-2,4-difluorobenzoic acidpreparation is used starting from 3-methoxy-2,4-difluoro-bromobenzene.

PRECURSOR EXAMPLE D

5-Bromo-3-chloro-2,4-difluorobenzoic acid

In a mixture of 50 ml of acetic acid, 10 ml of water and 13 ml of nitricacid is dissolved 2 g (0.014 mole) of 3-chloro-2,4-difluorobenzoic acidand 3.64 ml (0.028 mole) of bromine. A solution of 3.52 g (0.0208 mole)of silver nitrate in 10 ml of water is then added slowly. After 14 hoursat 20° C., the precipitate is filtered and rinsed with ether. Theorganic phase is washed with sodium bisulfite, then water and dried.Removal of the solvent affords the desired product.

PRECURSOR EXAMPLE E

5-Nitro-3-chloro-2,4-difluorobenzoic acid

An amount of 1 g of 3-chloro-2,4-difluorobenzoic acid is added to amixture of 1 ml of fuming nitric acid and 1.3 ml of sulfuric acid at 0°C. The suspension is then stirred at room temperature for 30 minutes andpoured on ice. Filtration affords the desired product.

The following is an example of the functionalization of a quinolone asdepicted in Scheme I above.

PRECURSOR EXAMPLE F

5-Bromo-3-chloro-2,4-difluorobenzoyl chloride

A quantity of 5.2 g of 5-bromo-3-chloro-2,4-difluorobenzoic acid issuspended in 30 ml of dichloromethane; then 2.92 g of oxalyl chloride isadded, and 3 drops of dry DMF are added. The mixture is stirred at roomtemperature for 3 hours and the desired compound is isolated afterevaporation of the solvent.

Ethyl 5-bromo-2,4-difluoro-3-chloro-benzoyl acetate

A quantity of 0.475 g of magnesium is suspended in 1.5 ml of ethanol and0.16 ml of carbon tetrachloride is added. A solution of 3 ml ofdiethylmalonate in 15 ml of ethanol is added dropwise and the mixture isstirred at 60° C. until complete dissolution of the magnesium. Themixture is cooled at −5° C. and 5.5 g of5-bromo-3-chloro-2,4-difluorobenzoyl chloride is added dropwise. Themixture is stirred at room temperature for 1 hour and 50 ml of diethylether, 20 ml of water are added; then the mixture is acidified withconcentrated hydrochloric acid. After separation of the organic phaseand removal of the solvent, the residue is suspended in 40 ml of waterand 0.1 g of PTSA is added. The suspension is refluxed for 2 hours,cooled at room temperature and extracted with diethyl ether. The desiredproduct is obtained after evaporation of the solvent.

Ethyl 3-cyclopropylamino-2-(5-bromo-2,4-difluoro-3-chloro-benzoyl)acrylate

A quantity of 6.2 g of ethyl 5-bromo-2,4-difluoro-3-chloro-benzoylacetate is dissolved in a mixture of 4.4 ml of acetic anhydride and 4.5ml of triethyl orthofomate. After 2 hours of reflux, excess reagent isevaporated, the residue is dissolved in 20 ml of ethanol and theresulting solution cooled at 0° C. A volume of 2 ml of cyclopropylamineis added and after 30 minutes the desired product is isolated byfiltration and air dried.

Ethyl6-bromo-1-cyclopropyl-1,4-dihydro-7-fluoro-8-chloro-4-oxo-quinoline-3-carboxylate

A quantity of 2.48 g of ethyl3-cyclopropylamino-2-(5-bromo-2,4-difluoro-3-chloro-benzoyl) acrylate isdissolved in 15 ml of THF and 0.27 g of 60% sodium hydride is addedportionwise. After 1 hour at room temperature, the suspension is pouredinto 100 ml of water and the desired product isolated by filtration andair dried.

Ethyl1-cyclopropyl-1,4-dihydro-7-fluoro-8-chloro-6-methyl-4-oxoquinoline-3-carboxyate

6-Bromo-8-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxyate(100 mg, 0.26 mmol), lithium chloride (0.033 g, 0.77 mmol),tris(dibenzylideneacetone)dipalladium (0) (0.024 g, 0.026 mmol),tetramethyltin (0.093 g, 0.52 mmol) and 5 mg of butylated hydroxytoluene(2,6-di-tert-butyl-4-methyl-phenol-BHT) were combined in 8 ml ofdimethyl formamide (DMF) and heated to 70-75° C. for 18 hours. Thesolvent is then removed in vacuo. The residue is triturated with hexanesand then chromatographed with 1% methanol in chloroform on silica toafford the desired product.

The following are examples of typical synthesis of an 8-methoxy and8-chloro quinolone of the subject invention as depicted in Scheme II.The last two steps allow variation at R7 by using a different amine.

Example G

Preparation of:

3-Methoxy-2-4-difluorobenzoyl chloride

A quantity of 43.9 g of 3-methoxy-2-4-difluorobenzoic acid is suspendedin 300 mL of dichloromethane and 25 mL of oxalyl chloride are addedfollowed by 4 drops of dry DMF. The mixture is stirred at roomtemperature for 6 hours and the solvent removed by evaporation to affordthe desired product.

Ethyl 2,4-difluoro-3-methoxy-benzoyl acetate

A quantity of 26.4 g of monoethyl malonate is dissolved in 700 mL ofTHF. The solution is cooled at −50° C. and 160 mL of 2.5 Mn-butyllithium is added keeping the temperature below −50° C. Thetemperature is initially raised to 0° C. and cooled back to −50° C. Anamount of 20.6 g of 3-methoxy-2-4-difluorobenzoyl chloride is addedkeeping the temperature at −50° C., then the reaction mixture is warmedto room temperature. Hydrochloric acid is added until the pH becomesacidic. The organic phase is washed with sodium bicarbonate and dried,evaporation of the solvent affords the desired product.

Ethyl 3-cyclopropylamino-2-(2,4-difluoro-3-methoxy-benzoyl) acrylate

To a mixture of 50 mL of acetic anhydride and 50 mL of triethylorthofomate is added 52.94 g of ethyl 2,4-difluoro-3-methoxy-benzoylacetate. The mixture is refluxed for 2 hours, then cooled to roomtemperature. The excess reagent is removed by evaporation to provide athick oil which is dissolved in 150 mL of ethanol. A quantity of 17.1 gof cyclopropylamine is then added while keeping the temperature about20° C. The desired product is isolated by filtration and air dried.

Ethyl1-cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylate

A quantity of 30.3 g of ethyl3-cyclopropylamino-2-(2,4-difluoro-3-methoxy-benzoyl) acrylate is addedto 230 mL of dry THF. An amount of 4.1 g of 60% sodium hydride in oil isadded portionwise keeping the temperature below 40° C. The solution isstirred at room temperature for 2 hours and then poured into 1.5 L ofwater. The desired product is isolated by filtration and air dried.

1-Cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylicacid

A quantity of 28.6 g ofethyl-1-cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylateand 300 mL of a mixture of acetic acid, water, sulfuric acid (8/6/1) arerefluxed for 2 hours. The reaction mixture is cooled at 0° C. and thedesired product collected by filtration.

1-Cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylicacid boron difluoride complex

A quantity of 1.0 g of1-cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylicacid is dissolved in 10 mL of THF and 1.76 mL of boron trifluorideetherate is added. The mixture is stirred at 60° C. for 2 hours thencooled to room temperature. The desired product is collected byfiltration and air dried.

7-[(3R)-(1S-tert-Butoxycarbonylaminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

A quantity of 0.1 g of1-cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylicacid boron difluoride complex is dissolved in 2 mL of acetonitrile;then, 0.16 mL of diisopropylethylamine and 0.08 g of3R-(1S-tert-Butoxycarbonylaminoethyl)pyrrolidine are added. The mixtureis stirred at 60° C. for 24 hours, and then the solvent is removed byevaporation. The residue is dissolved in 5 mL of ethanol and 2 mL oftriethylamine. The solution is stirred at 80° C. for 4 hours, thenevaporated to dryness. The desired compound is isolated by columnchromatography.

7-[(3R)-(1S-Aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid hydrochloride

A quantity of 54 mg of7-[(3R)-(1S-tert-Butoxycarbonylaminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid is dissolved in 2 mL of ethanol and 0.5 mL of concentratedhydrochloric acid. After half an hour at room temperature the desiredcompound is collected by filtration after cooling the mixture in an icebath.

EXAMPLE H

Preparation of:

3-Chloro-2,4-difluorobenzoyl chloride

A quantity of 6.0 g of 3-chloro-2,4-difluorobenzoic acid is suspended in20 ml of dichloromethane. A quantity of 2.99 ml of oxalyl chloride and 2drops of DMF are then added. The suspension is stirred at roomtemperature overnight and the desired product is collected afterevaporation of the solvent.

Ethyl 2,4-difluoro-3-chloro-benzoyl acetate

A quantity of 0.728 g of magnesium is suspended in 5 ml of ethanol and0.1 ml of carbon tetrachloride is added. A solution of 4.6 ml of diethylmalonate in 20 ml of ethanol is added and the reaction is stirred at 60°C. until complete dissolution of the magnesium. Then 6.1 g of3-chloro-2,4-difluorobenzoyl chloride are added and the reaction stirredovernight. After evaporation of the solvent, the residue is treated withhydrochloric acid and the organic extracted by ethyl acetate. Afterevaporation of the solvent the residue is suspended in 50 ml of waterand 100 mg of PTSA is added. The suspension is refluxed for 4 hours thencooled to room temperature. The desired compound is extracted with ethylacetate and recovered by evaporation of the solvent.

Ethyl 3-cyclopropylamino-2-(2,4-difluoro-3-chloro-benzoyl) acrylate

To a mixture of 7.03 ml of triethyl orthoformate and 6.65 ml of aceticanhydride is added 7.6 g of ethyl 2,4-difluoro-3-chloro-benzoyl acetate.The solution is refluxed for 4 hours and the excess of reagent removedby evaporation. The residual thick oil is dissolved in a mixture of 10ml of ethanol and 2 ml of diethyl ether and cooled in an ice bath.Cyclopropylamine (1.3 ml) is then added. After 30 minutes at roomtemperature the desired product is isolated by filtration.

Ethyl1-cyclopropyl-1,4-dihydro-7-fluoro-8-chloro-4-oxo-quinoline-3-carboxylate

A quantity of 2.8 g of ethyl3-cyclopropylamino-2-(2,4-difluoro-3-chlorobenzoyl) acrylate isdissolved in 25 ml of THF and 0.37 g of 60% sodium hydride is addedportion wise. After 30 minutes, the solvent is evaporated; the residueis redissolved in ethyl acetate and washed with water. The desiredproduct is collected by removal of the solvent.

1-Cyclopropyl-1,4-dihydro-7-fluoro-8-chloro-4-oxo-quinoline-3-carboxylicacid

A quantity of 1.93 g ofethyl-1-cyclopropyl-1,4-dihydro-7-fluoro-8-chloro-4-oxo-quinoline-3-carboxylateis dissolved in 30 ml of a mixture of acetic acid, water and sulfuricacid (8/6/1). the mixture is refluxed for 3 hours and cooled to roomtemperature. The desired compound is collected by filtration and airdried.

7-[(3R)-(1S-tert-Butoxycarbonylaminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

A quantity of 0.1 g of1-cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylicacid boron difluoride complex is dissolved in 2 mL of acetonitrile; then0.16 mL of diisopropylethylamine and 0.08 g of3R-(1S-tert-Butoxycarbonylaminoethyl)pyrrolidine are added. The mixtureis stirred at 60° C. for 24 hours, and then the solvent removed byevaporation. The residue is dissolved in 5 mL of ethanol and 2 mL oftriethylamine. The solution is stirred at 80° C. for 4 hours, thenevaporated to dryness. The desired compound is isolated by columnchromatography.

7-[(3R)-(1S-Aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid hydrochloride

A quantity of 54 mg of7-[(3R)-(1S-tert-Butoxycarbonylaminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid is dissolved in 2 mL of ethanol and 0.5 mL of concentratedhydrochloric acid. After half an hour at room temperature, the mixtureis cooled in an ice bath, and the desired compound is collected byfiltration.

EXAMPLE J

Preparation of:

7-[3R-(1S-Methylaminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid methanesulfonate

A quantity of 1.775 g of1-cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylicacid boron difluoride ester is dissolved in 12 ml of dimethylformamide;then 3.35 ml of triethylamine and 1.050 g of3R-(1S-methylaminoethyl)-1-pyrrolidine are added. The mixture is stirredat 50° C. for 18 hours and the solvent removed by evaporation. Theresidue is redissolved in 20 ml of ethanol and 7 ml of triethylamine.The solution is refluxed at 80° C. for 24 hours, and then evaporated todryness. The desired material is isolated by recrystallization fromisopropanol and methanol. This material is suspended in 15 mL of ethanoland warmed slightly. The suspension is treated with 0.3 mL ofmethanesulfonic acid and stirred for 2 hours at room temperature. Themixture is cooled in an ice bath, and the desired compound is collectedby filtration.

EXAMPLE K

Preparation of:

1-Benzyl-4R-(1S-tert-Butoxycarbonylaminoethyl)-2-pyrrolidinone

Sodium hydride (60% dispersion in mineral oil, 1.06 g, 26.4 mmol) issuspended in DMF. 4R-(1S-tert-Butoxycarbonylaminoethyl)-2-pyrrolidinone(5.04 g, 22.0 mmol) is added as a solution in DMF over the course offive minutes. The solution is allowed to stir for one hour after whichbenzyl bromide (3.76 g, 22.0 mmol) is added, and the solution is allowedto stir overnight. The DMF is removed under reduced pressure and theremaining solid partitioned between water and ethyl acetate. The organiclayer is removed and the water layer is extracted twice with ethylacetate. The combined organic layers are washed once with brine, driedover sodium sulfate and evaporated to yield a white solid.

1-Benzyl-4R-(1S-aminoethyl)-2-pyrrolidinone

1-Benzyl-4R-(1S-tert-Butoxycarbonylaminoethyl)-2-pyrrolidinone (6.57 g,20.6 mmol) is dissolved in 40 ml of absolute ethanol and 10 ml of 12NHCl is added with stirring. The solution is stirred for two hours, atwhich time the solution is brought to greater than pH 12 by addition ofammonium hydroxide. The solution is extracted three times with 300 ml ofdichloromethane. The organic portions are dried over sodium sulfate andevaporated to yield an amber oil

1-Benzyl-4-(2′,2′,5′,5′-tetramethyl-2′,5′-disila-1′-azacyclopentyl)ethyl-2-pyrrolidinone

1-Benzyl-4R-(1S-aminoethyl)-2-pyrrolidinone (2.47 g, 11.3 mmol) isdissolved in 25 ml of dichloromethane and 12 ml ofdiisopropylethylamine. Bis(chlorodimethylsilyl)ethane (4.88 g, 22.6mmol) is added, and the reaction is stirred under argon for three hours.The reaction is quenched by addition of saturated ammonium chloride andwashed twice with water. The dichloromethane is removed and the residueredissolved in ether and any solid filtered away. The ether is removedin vacuo to yield a reddish oil.

4-Benzyl-6-(2′,2′,5′,5′-tetramethyl-2′,5′-disila-1′-azacyclopentyl)ethyl-4-azaspiro[2.4]heptane

A mixture of 160 ml of THF and 38 ml of 1M ethylmagnesium bromide in THF(38.0 mmol) is brought to −70° C. Titanium isopropoxide (4.85 g, 17.1mmol) is added quickly and the solution turns a light orange. After twominutes,1-benzyl-4-(2′,2′,5′,5′-tetramethyl-2′,5′-disila-1′-azacyclopentyl)ethyl-2-pyrrolidinone(3.85 g, 10.7 mmol) in THF is added dropwise. The resulting mixture isstirred for 15 minutes at −70° C. and then allowed to warm to roomtemperature for two hours. The reaction is quenched by addition of 200ml of half saturated ammonium chloride; the resulting slurry isfiltered. The filtrate is extracted three times with 150 ml of ether.The combined organic layers are washed with brine, dried over sodiumsulfate, and evaporated to yield a light yellow oil.

4-Benzyl-6R-(1S-t-Butoxycarbonylaminoethyl)-4-azaspiro[2.4]heptane

4-Benzyl-6-(2′,2′,5′,5′-tetramethyl-2′,5′-disila-1′-azacyclopentyl)ethyl-4-azaspiro[2.4]heptane(0.89 g, 2.4 mmol) is dissolved in 10 ml of absolute ethanol and 5 ml ofglacial acetic acid. After stirring for an hour, the solvent is removedin vacuo, and the sample is redissolved in ethanol and treated withdi-tert-butyl dicarbonate (1.05 g, 4.8 mmol) and triethylamine (0.49 g,4.8 mmol). The mixture is allowed to stir overnight. Solvent and excesstriethylamine are evaporated off and the residue is subjected to flashchromatography (3:2 hexane/ethyl acetate v/v) to obtain the desiredcompound.

3R-(1S-tert-Butoxycarbonylaminoethyl)-5-ethylpyrrolidine

4-Benzyl-6R-(1S-t-Butoxycarbonylaminoethyl)-4-azaspiro[2.4]heptane (0.31g, 0.9 mmol) is dissolved in 5 ml of methanol is mixed with palladiumhydroxide on carbon (0.10 g) and palladium on activated carbon (0.05 g).The mixture is placed under a hydrogen atmosphere at 44 psi and shakenovernight. The solution is then filtered to remove catalyst, and thefiltrate is concentrated to yield3-tert-Butoxycarbonylaminoethyl-5-ethylpyrrolidine as a clear oil.

7-[3R-(1S-tert-Butoxycarbonylaminoethyl)-5-ethyl-1-pyrrolidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid, boron difluoride ester

3R-(1S-tert-Butoxycarbonylaminoethyl)-5-ethylpyrrolidine (0.17 g, 0.7mmol) is dissolved in DMF and stirred in the presence of1-cyclopropyl-7-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid, boron difluoride ester (0.13 g, 0.4 mmol) and triethylamine at 40°C. for several hours until the reaction is complete. The solvent isremoved in vacuo and the residue triturated with water to yield thetargeted compound as a solid.

7-[3R-(1S-tert-Butoxycarbonylaminoethyl)-5-ethyl-1-pyrrolidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid

7-[3R-(1S-tert-Butoxycarbonylaminoethyl)-5-ethyl-1-pyrrolidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid, boron difluoride ester (0.20 g, 0.4 mmol) is stirred in a solutionof 1:1 ethanol/triethylamine for several hours until the removal of theboronate ester is complete. The solvent is evaporated in vacuo and theresidue triturated with water to yield the desired product.

7-[3R-(1S-Aminoethyl)-5-ethyl-1-pyrrolidinyl]-1-cycloproply-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid hydrochloride

7-[3R-(1S-tert-Butoxycarbonylaminoethyl)-5-ethyl-1-pyrrolidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid (0.18 g, 0.4 mmol) is stirred in a 1:1 mixture of ethanol andconcentrated HCl until the reaction is complete. The solvent is removedin vacuo and the residue purified by recrystallization from ethanol.

EXAMPLE L

Preparation of:

3-Amino-4-methylpiperidine

A quantity of 5.0 g of 3-nitro-4-methylpyridine, 0.5 g of rutheniumoxide, 0.5 g of rhodium on aluminia, and 0.5 g of platinum oxide aresuspended in 20 ml of ammonia solution and 10 ml of methanol. Themixture is subjected to high temperature and high pressure hydrogen gas.The desired product is obtained by an aqueous work up.

7-[3-Amino-4-methylpiperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylicacid boron difluoride complex

Quantities of 2.62 g of1-cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylicacid boron difluoride complex and 1.38 g of 3-amino-4-methylpiperidineare dissolved in 48.0 mL of dimethylformamide and 4.50 mL oftriethylamine. After overnight at room temperature, the solution isevaporated to dryness. The desired product is isolated byrecrystallization.

7-[3-Amino-4-methylpiperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylicacid

A quantity of 0.263 g of7-[3-amino-4-methylpiperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylicacid boron difluoride complex is dissolved in 6 mL of ethanol, and 1.75mL of triethylamine is added. The solution is heated to reflux for 2hours, then cooled to room temperature. The solution is evaporated todryness, and the desired product is isolated by recrystallization.

7-[3-Amino-4-methylpiperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylicacid hydrochloride salt

A quantity of 0.20 g of7-[3-amino-4-methylpiperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylicacid is suspended in 1.0 mL of ethanol. Its pH is adjusted to 2 withhydrogen chloride to obtain the desired product after the evaporation ofsolvent.

EXAMPLE M

Preparation of:

Ethyl 2-(2,4-difluoro-3-methoxy benzoyl)-3-ethylaminoacrylate

To a mixture of 3.7 ml of acetic anhydride and 4.3 ml of triethylorthoformate (26 mmol) is added 4.15 g of ethyl2,4-difluoro-3-methoxy-benzoyl acetate (16 mmol). The mixture isrefluxed for 4 hours, cooled to room temperature and the excess reagentis removed under reduced pressure to provide a thick oil. The product isused without further purification by dissolving it in 12 ml of absoluteethanol. A quantity of 8 ml of ethylamine (2.0 M solution in THF) isthen added at 0° C. and stirred overnight at room temperature. Thedesired product is isolated by filtration and washing with cold ethanol.

Ethyl1-ethyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylate

Ethyl 2-(2,4-difluoro-3-methoxy)-3-ethylaminoacrylate (1.75 g, 5.6 mmol)is added to anhydrous THF under nitrogen atmosphere. The mixture iscooled to 0° C. in an ice bath. Sodium hydride (335 mg, 8.3 mmol) isadded portionwise over 2 minutes maintaining the temperature of thereaction below 10° C. The reaction is warmed to room temperature andstirred for additional 50 minutes and cooled to 0° C. Careful additionof water quenches the reaction, which is extracted with dichloromethane.The organic layer is washed twice with brine, dried over MgSO₄, andconcentrated under reduced pressure to yield the desired compound as asolid.

1-Ethyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid

Ethyl1-ethyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylate(1.37 g, 4.7 mmol) is suspended in a mixture of acetic acid: water:sulfuric acid (8:6:1). The mixture is refluxed for 3 hours, and thencooled to room temperature. The crystals are filtered and rinsed withcold water.

1-Ethyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid,boron difluoride ester

To 1-ethyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylicacid (985 mg, 3.7 mmol) dissolved in anhydrous THF (10 ml) is addedboron trifuloride ethrate (940 ml, 7.4 mmol). The mixture is heated to65° C. for 4 hours and allowed to cool to room temperature overnight.The filtered crystals are washed with hexanes to afford the desiredproduct.

7-[3R-(1S-tert-Butoxycarbonylaminoethyl)-1-pyrrolidinyl]-1-ethyl-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid

1-Ethyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acidboron difluoride ester (0.17 g, 0.5 mmol),3R-(1S-tert-Butoxycarbonylaminoethyl)-pyrrolidine 0.11 g, 0.5 mmol) andtriethylamine (0.3 ml, 2.0 mmol) are dissolved in 5 ml of DMF. Themixture is stirred at 60° C. for 24 hours, and the solvent is removedunder reduced pressure. The solid obtained from the filtration is washedwith small amount of water and re-dissolved in 5 ml of methanol with 1ml of triethylamine. The solution is heated at 70° C. for 6 hours andthen evaporated to dryness to afford the desired product.

7-[3R-(1S-Aminoethyl)-1-pyrrolidinyl]-1-ethyl-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid hydrochloride

A quantity of 110 mg of7-[3R-(1S-tert-Butoxycarbonylaminoethyl)-1-pyrrolidinyl]-1-ethyl-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid is dissolved in 2 ml of ethanol and 2 ml of concentratedhydrochloric acid. After two hours at room temperature, the solid isobtained after the evaporation of the solvent and recrystallization inethanol.

EXAMPLE N

Preparation of:

7-[3-Aminopiperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylicacid boron difluoride complex

Quantities of 2.62 g of1-cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylicacid boron difluoride complex and 2.08 g of 3-aminopiperidinedihydrochloride salt are mixed in 48.0 mL of dimethylformamide and 4.50mL of triethylamine. After overnight stirring at room temperature, thesolution is cooled and filtered to give the desired product.

7-[3-Aminopiperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylicacid

A quantity of 0.253 g of7-[3-aminopiperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylicacid boron difluoride complex is dissolved in 6 mL of ethanol, and 1.75mL of triethylamine is added. The solution is heated to reflux for 2hours and the mixture is evaporated to dryness under reduced pressure.The desired product is isolated by recrystallization.

7-[3-Aminopiperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylicacid dihydrochloride salt

A quantity of 0.19 g of7-[3-aminopiperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carboxylicacid is suspended in 1.0 mL of ethanol. The pH of the solution isadjusted to 2 with the addition of hydrogen chloride. The desiredproduct is obtained by evaporation of the solvent.

COMPOSITIONS OF THE INVENTION

The compositions of this invention comprise:

(a) a safe and effective amount of the compound of the invention

(b) a pharmaceutically-acceptable excipient.

It may also optionally comprise other antimicrobials or other actives,which may or may not act synergystically with the invention.

A “safe and effective amount” of a quinolone is an amount that iseffective, to inhibit microbial growth at the site of an infection to betreated in a host, without undue adverse side effects (such as toxicity,irritation, or allergic response), commensurate with a reasonablebenefit/risk ratio when used in the manner of this invention. Thespecific “safe and effective amount” will vary with such factors as theparticular condition being treated, the physical condition of thepatient, the duration of treatment, the nature of concurrent therapy (ifany), the specific dosage form to be used, the excipient employed, thesolubility of the quinolone therein, and the dosage regimen desired forthe composition.

The compositions of this invention are preferably provided in unitdosage form. As used herein, a “unit dosage form” is a composition ofthis invention containing an amount of a quinolone that is suitable foradministration to a human or lower animal subject, in a single dose,according to good medical practice. These compositions preferablycontain from about 30 mg, more preferably from about 50 mg, morepreferably still from about 100 mg, preferably to about 20,000 mg, morepreferably to about 7,000 mg, more preferably still to about 1,000 mg,most preferably to about 500 mg, of a quinolone.

The compositions of this invention may be in any of a variety of forms,suitable (for example) for oral, rectal, topical or parenteraladministration. Depending upon the particular route of administrationdesired, a variety of pharmaceutically-acceptable excipients well-knownin the art may be used. These include solid or liquid fillers, diluents,hydrotropes, surface-active agents, and encapsulating substances.Optional pharmaceutically-active materials may be included, which do notsubstantially interfere with the antimicrobial activity of thequinolone. The amount of excipient employed in conjunction with thequinolone is sufficient to provide a practical quantity of material foradministration per unit dose of the quinolone. Techniques andcompositions for making dosage forms useful in the methods of thisinvention are described in the following references, all incorporated byreference herein: Modern Pharmaceutics, Vol. 7, Chapters 9 and 10(Banker & Rhodes, editors, 1979); Lieberman et al., PharmaceuticalDosage Forms: Tablets (1981); and Ansel, Introduction to PharmaceuticalDosage Forms 2d Edition (1976).

In particular, pharmaceutically-acceptable excipients for systemicadministration include sugars, starches, cellulose and its derivatives,malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils,polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonicsaline, and pyrogen-free water. Preferred excipients for parenteraladministration include propylene glycol, ethyl oleate, pyrrolidone,ethanol, and sesame oil. Preferably, the pharmaceutically-acceptableexcipient, in compositions for parenteral administration, comprises atleast about 90% by weight by the total composition.

In addition, dosages for injection may be prepared in dried orlyophilized form. Such forms can be reconstituted with water or salinesolution, depending on the preparation of the dosage form. Such formsmay be packaged as individual dosages or multiple dosages for easierhandling. Where lyophilized or dried dosages are used, the reconstituteddosage form is preferably isotonic, and at a physiologically compatiblepH.

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. These oral forms comprisea safe and effective amount, usually at least about 5%, and preferablyfrom about 25% to about 50%, of the quinolone. Tablets can becompressed, tablet triturates, enteric-coated, sugar-coated,film-coated, or multiple-compressed, containing suitable binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, flow-inducing agents, and melting agents. Liquid oral dosageforms include aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules, andeffervescent preparations reconstituted from effervescent granules,containing suitable solvents, preservatives, emulsifying agents,suspending agents, diluents, sweeteners, melting agents, coloring agentsand flavoring agents, such are well known to the skilled artisan.Preferred excipients for oral administration include gelatin, propyleneglycol, cottonseed oil and sesame oil.

The compositions of this invention can also be administered topically toa subject, i.e., by the direct laying on or spreading of the compositionon the epidermal or epithelial tissue of the subject. Such compositionsinclude, for example, lotions, creams, solutions, gels and solids. Thesetopical compositions preferably comprise a safe and effective amount,usually at least about 0.1%, and preferably from about 1% to about 5%,of the quinolone. Suitable excipients for topical administrationpreferably remain in place on the skin as a continuous film, and resistbeing removed by perspiration or immersion in water. Generally, theexcipient is organic in nature and capable of having dispersed ordissolved therein the quinolone. The excipient may includepharmaceutically-acceptable emolients, emulsifiers, thickening agents,and solvents and the like; these are well known to the skilled artisan.

METHODS OF USING THE COMPOUNDS

This invention also provides methods of treating or preventing aninfectious disorder in a human or other animal subject, by administeringa safe and effective amount of a quinolone to said subject. As usedherein, an “infectious disorder” is any disorder characterized by thepresence of a microbial infection. Preferred methods of this inventionare for the treatment of bacterial infections. Such infectious disordersinclude (for example) central nervous system infections, external earinfections, infections of the middle ear (such as acute otitis media),infections of the cranial sinuses, eye infections, infections of theoral cavity (such as infections of the teeth, gums and mucosa), upperrespiratory tract infections, lower respiratory tract infections,including pneumonia, genitourinary infections, gastrointestinalinfections, gynecological infections, septicemia, sepsis, peritonitis,bone and joint infections, skin and skin structure infections, bacterialendocarditis, burns, antibacterial prophylaxis of surgery, andantibacterial prophylaxis in post-operative patients or inimmunosuppressed patients (such as patients receiving cancerchemotherapy, or organ transplant patients).

The quinolone derivatives and compositions of this invention can beadministered topically or systemically. Systemic application includesany method of introducing the quinolone into the tissues of the body,e.g., intrathecal, epidural, intramuscular, transdermal, intravenous,intraperitoneal, subcutaneous, sublingual, rectal, and oraladministration. The specific dosage of antimicrobial to be administered,as well as the duration of treatment, are mutually dependent. The dosageand treatment regimen will also depend upon such factors as the specificquinolone used, the resistance pattern of the infecting organism to thequinolone used, the ability of the quinolone to reach minimum inhibitoryconcentrations at the site of the infection, the nature and extent ofother infections (if any), the personal attributes of the subject (suchas weight), compliance with the treatment regimen, the age and healthstatus of the patient, and the presence and severity of any side effectsof the treatment.

Typically, for a human adult (weighing approximately 70 kilograms), fromabout 75 mg, more preferably from about 200 mg, most preferably fromabout 500 mg to about 30,000 mg, more preferably to about 10,000 mg,most preferably to about 3,500 mg, of quinolone is administered per day.Treatment regimens preferably extend from about 1, preferably from about3 to about 56 days, preferably to about 20 days, in duration.Prophylactic regimens (such as avoidance of opportunistic infections inimmunocompromised patients) may extend 6 months, or longer, according togood medical practice.

A preferred method of parenteral administration is through intravenousinjection. As is known and practiced in the art, all formulations forparenteral administration must be sterile. For mammals, especiallyhumans, (assuming an approximate body weight of 70 kilograms) individualdoses of from about 100 mg, preferably from about 500 mg to about 7,000mg, more preferably to about 3,500 mg, is acceptable.

In some cases, such as generalized, systemic infections or inimmune-compromised patients, the invention may be dosed intravenously.The dosage form is generally isotonic and at physiological pH. Thedosage amount will depend on the patient and severity of condition, aswell as other commonly considered parameters. Determination of suchdoses is well within the scope of practice for the skilled practitionerusing the guidance given in the specification.

A preferred method of systemic administration is oral administration.Individual doses of from about 20 mg, more preferably from about 100 mgto about 2,500 mg, more preferably to about 500 mg.

Topical administration can be used to deliver the quinolonesystemically, or to treat a local infection. The amounts of quinolone tobe topically administered depends upon such factors as skin sensitivity,type and location of the tissue to be treated, the composition andexcipient (if any) to be administered, the particular quinolone to beadministered, as well as the particular disorder to be treated and theextent to which systemic (as distinguished from local) effects aredesired.

The following non-limiting examples illustrate the compounds,compositions, processes, and uses of the present invention.

COMPOSITION EXAMPLE P

A tablet composition for oral administration, according to the presentinvention, is made comprising:

Component Amount Compound of Example 15 150 mg Lactose 120 mg MaizeStarch 70 mg Talc 4 mg Magnesium Stearate 1 mg

Other compounds having a structure according to Formula 1 are used withsubstantially similar results.

COMPOSITION EXAMPLE Q

A capsule containing 200 mg of active for oral administration, accordingto the present invention, is made comprising:

Component Amount (% w/w) Compound of Example 18  15% Hydrous Lactose 43% Microcrystalline Cellulose  33% Crosspovidone 3.3% MagnesiumStearate 5.7%

Other compounds having a structure according to Formula 1 are used withsubstantially similar results.

COMPOSITION EXAMPLE R

A saline-based composition for ocular administration, according to thepresent invention, is made comprising:

Component Amount (% w/w) Compound of Example 63 10% Saline 90%

Other compounds having a structure according to Formula 1 are used withsubstantially similar results.

COMPOSITION EXAMPLE S

A intranasal composition for local administration, according to thepresent invention, is made comprising:

Component Composition (% w/v) Compound of Example 24 0.20 Benzalkoniumchloride 0.02 EDTA 0.05 Glycerin 2.0 PEG 1450 2.0 Aromatics 0.075Purified water q.s.

Other compounds having a structure according to Formula 1 are used withsubstantially similar results.

COMPOSITION EXAMPLE T

A inhalation aerosol composition, according to the present invention, ismade comprising:

Component Composition (% w/v) Compound of Example 84 5.0 Ascorbic acid0.1 Menthol 0.1 Sodium Saccharin 0.2 Propellant (F12, F114) q.s.

Other compounds having a structure according to Formula 1 are used withsubstantially similar results.

COMPOSITION EXAMPLE U

A topical opthalmic composition, according to the present invention, ismade comprising:

Component Composition (% w/v) Compound of Example 47 0.10 Benzalkoniumchloride 0.01 EDTA 0.05 Hydroxyethylcellulose 0.5 Acetic acid 0.20Sodium metabisulfite 0.10 Sodium chloride (0.9%) q.s.

Other compounds having a structure according to Formula 1 are used withsubstantially similar results.

COMPOSITION EXAMPLE V

An antimicrobial composition for parenteral administration, according tothis invention, is made comprising:

Component Amount Compound of Example 93 30 mg/ml excipient Excipient: 50mm phosphate buffer pH 5 buffer with lecithin 0.48%carboxymethylcellulose 0.53 povidone 0.50 methyl paraben 0.11 propylparaben 0.011

The above ingredients are mixed, forming a suspension. Approximately 2.0ml of the suspension is systemically administered, via intramuscularinjection, to a human subject suffering from a lower respiratory tractinfection, with Streptococcus pneumoniae present. This dosage isrepeated twice daily, for approximately 14 days. After 4 days, symptomsof the disease subside, indicating that the pathogen has beensubstantially eradicated. Other compounds having a structure accordingto Formula 1 are used with substantially similar results.

COMPOSITION EXAMPLE W

An enteric coated antimicrobial composition for oral administration,according to this invention, is made comprising the following coretablet:

Component Amount (mg) Compound of Example 17 350.0 Maltodextrine 30.0Magnesium Stearate 5.0 Microcrystalline Cellulose 100.0 ColloidalSilicon Dioxide 2.5 Povidone 12.5

The components are admixed into a bulk mixture. Compressed tablets areformed, using tabletting methods known in the art. The tablet is thencoated with a suspension of methacrylic acid/methacrylic acid esterpolymer in isopropanol/acetone. A human subject, having a urinary tractinfection with Escherichia coli present, is orally administered two ofthe tablets, every 8 hours, for 4 days. Symptoms of the disease thensubside, indicating substantial eradication of the pathogen. Othercompounds having a structure according to Formula 1 are used withsubstantially similar results.

All references described herein are hereby incorporated by reference.

While particular embodiments of the subject invention have beendescribed, it will be obvious to those skilled in the art that variouschanges and modifications of the subject invention can be made withoutdeparting from the spirit and scope of the invention. It is intended tocover, in the appended claims, all such modifications that are withinthe scope of this invention.

What is claimed is:
 1. A compound having the following formula:

wherein: (a) X is selected from the group consisting of

(b) R1 is selected from the group consisting of C₃ to about C₅cycloalkyl, C₁ to about C₂ alkanyl, C₂ to about C₃ linear alkenyl, C₃ toabout C₄ branched alkanyl or alkenyl, all such alkyl or cycloalkylmoieties being unsubstituted or substituted with from 1 to about 3fluoro; and phenyl, unsubstituted or substituted with from 1 to about 3fluoro, or with one hydroxy in the 4-position; (c) R3 is hydrogen orhydroxy; (d) R5 is selected from the group consisting of hydrogen,hydroxy, amino, halo, C₁ to about C₂ alkanyl, C₂ alkenyl, and methoxy,all such alkyl and methoxy moieties being unsubstituted or substitutedwith from 1 to about 3 fluoro; (e) R6 is selected from the groupconsisting of hydrogen, hydroxy, aminocarbonyl, bromo, cyano, C₁ toabout C₂ alkanyl, C₂ to about C₄ alkenyl or alkynyl, all such alkylmoieties being unsubstituted or substituted with from 1 to about 3fluoro, or such methyl or ethyl moieties being optionally substitutedwith one hydroxy or amino; (f) R8 is methoxy, methylthio, or C₁ to aboutC₂ alkanyl unsubstituted or substituted with from 1 to about 3 fluoro;(g) R7 is amino which is attached to a ring carbon of X which is notadjacent to the ring nitrogen, the amino being unsubstituted orsubstituted with one or two C₁ to about C₃ alkanyl; or aminoalkanylwhich is attached to any ring carbon of X and is C₁ to about C₃ alkanylsubstituted with one amino, the amino being unsubstituted or substitutedwith one or two C₁ to about C₃ alkanyl; (h) each R9 is independentlyselected from the group consisting of hydrogen, C₁ to about C₄ alkanyl,C₂ to about C₆ alkenyl or alkynyl, and a C₃ to about C₆ fused orspirocycle alkyl ring; or one R9 may optionally be selected from thegroup consisting of hydroxy, C₁ to about C₄ alkoxy, aryl and heteroaryl,all other R9 being hydrogen; all alkyl and aryl portions of R9 moietiesbeing unsubstituted or substituted with one hydroxy or with from 1 toabout 3 fluoro; and (j) a R7 moiety described in (g) and a R9 moietydescribed in (h) may optionally be connected thus forming a spirocyclering with the N-containing ring shown in (a), the spirocycle ringcomprising from 2 to about 5 ring carbons and 0 or 1 ring nitrogen; anoptical isomer, diastereomer or enantiomer thereof; apharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester,amide or imide thereof.
 2. A compound having the following formula:

wherein: (a) X is selected from the group consisting of

(b) R1 is selected from the group consisting of C₃ to about C₅cycloalkyl, C₁ to about C₂ alkanyl, C₂ to about C₃ linear alkenyl, C₃ toabout C₄ branched alkanyl or alkenyl, all such alkyl or cycloalkylmoieties being unsubstituted or substituted with from 1 to about 3fluoro; and phenyl, unsubstituted or substituted with from 1 to about 3fluoro, or with one hydroxy in the 4-position; (c) R3 is hydrogen orhydroxy; (d) R5 is selected from the group consisting of hydrogen,hydroxy, amino, halo, C₁ to about C₂ alkanyl, C₂ alkenyl, and methoxy,all such alkyl and methoxy moieties being unsubstituted or substitutedwith from 1 to about 3 fluoro; (e) R6 is hydrogen; (f) R8 is methoxy ormethylthio, unsubstituted or substituted with from 1 to about 3 fluoro;(g) R7 is amino which is attached to a ring carbon of X which is notadjacent to the ring nitrogen, the amino being unsubstituted orsubstituted with one or two C₁ to about C₃ alkanyl; or aminoalkanylwhich is attached to any ring carbon of X and is C₁ to about C₃ alkanylsubstituted with one amino, the amino being unsubstituted or substitutedwith one or two C₁ to about C₃ alkanyl; (h) each R9 is independentlyselected from the group consisting of hydrogen, C₁ to about C₄ alkanyl,C₂ to about C₆ alkenyl or alkynyl, and a C₃ to about C₆ fused orspirocycle alkyl ring; or one R9 may optionally be selected from thegroup consisting of hydroxy, C₁ to about C₄ alkoxy, aryl and heteroaryl,all other R9 being hydrogen; all alkyl and aryl portions of R9 moietiesbeing unsubstituted or substituted with one hydroxy or with from 1 toabout 3 fluoro; and (j) a R7 moiety described in (g) and a R9 moietydescribed in (h) may optionally be connected thus forming a fused orspirocycle ring with the N-containing ring shown in (a), the fused orspirocycle ring comprising from 2 to about 5 ring carbons and 0 or 1ring nitrogen; an optical isomer, diastereomer or enantiomer thereof; apharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester,amide or imide thereof.
 3. The compound of claim 2 wherein R3 ishydroxy, and X is


4. The compound of claim 3 wherein: (a) R1 is selected from the groupconsisting of C₃ to C₅ cycloalkanyl, methyl, ethyl, ethenyl, isopropyl,isopropenyl, isobutyl, isobutenyl, t-butyl, all such alkyl orcycloalkanyl moieties being unsubstituted or substituted with from 1 to3 fluoro; and phenyl, unsubstituted or substituted with from 1 to 3fluoro, or with one hydroxy in the 4-position; (b) R5 is selected fromthe group consisting of hydrogen, hydroxy, amino, fluoro, chloro, bromo,and methyl, the methyl being unsubstituted or substituted with from 1 to3 fluoro; (c) R8 is methoxy, unsubstituted or substituted with from 1 to3 fluoro (d) R7 is attached to a ring carbon of X which is not adjacentto the ring nitrogen; and (e) no more than two ring carbons of X havenon-hydrogen R9's attached thereto.
 5. The compound of claim 4 wherein:(a) R1 is selected from the group consisting of cyclopropyl, ethyl,phenyl substituted with 1 to 3 fluoro, and 4-hydroxyphenyl; (b) R5 isselected from the group consisting of hydrogen, hydroxy, chloro, bromo,amino, and methyl, the methyl being unsubstituted or substituted withfrom 1 to 3 fluoro; (c) when X comprises the piperidinyl ring, R7 isamino unsubstituted or substituted with one C₁ to C₃ alkanyl or twomethyl; when X comprises the pyrrolidinyl ring, R7 is aminoalkanyl whichis methyl or ethyl or isopropyl substituted with one amino unsubstitutedor substituted with one methyl or ethyl or dimethyl.
 6. The compound ofclaim 5 wherein: (a) R1 is cyclopropyl or ethyl, unsubstituted orsubstituted with from 1 to about 3 fluoro; (b) R5 is selected from thegroup consisting of hydrogen, hydroxy, amino, and methyl; (c) R8 isunsubstituted methoxy; (d) when X comprises the piperidinyl ring, R7 isamino or methylamino in the 3-position or 4-position of the ring; when Xcomprises the pyrrolidinyl ring, R7 is selected from the groupconsisting of aminomethyl, methylaminomethyl, 1-aminoethyl,1-methylaminoethyl, 1-amino-1-methylethyl and1-methylamino-1-methylethyl in the 3-position of the ring (e) all R9 arehydrogen or only one ring carbon of X has a non-hydrogen R9 attachedthereto, such non-hydrogen R9 being selected from the group consistingof methyl, ethyl, dimethyl and spirocyclopropyl.
 7. The compound ofclaim 6 wherein X comprises the pyrrolidinyl ring.
 8. The compound ofclaim 7 wherein R1 is cyclopropyl, R5 is hydrogen, and all R9 arehydrogen.
 9. The compound of claim 4 wherein; (a) R1 is selected fromthe group consisting of cyclopropyl, ethyl, phenyl substituted with 1 to3 fluoro, and 4-hydroxyphenyl; (b) R5 is selected from the groupconsisting of hydrogen, hydroxy, amino, and methyl; (c) R8 isunsubstituted methoxy; (d) X comprises the piperidinyl ring; (e) R7 isamino in the 3-position of the piperidinyl ring; and (f) all R9 arehydrogen, or one non-hydrogen R9 is in the 4-position or 5-position ofthe piperidinyl ring.
 10. The compound of claim 9 wherein: (a) R1 iscyclopropyl, (b) R5 is hydrogen, and (c) all R9 are hydrogen, or onenon-hydrogen R9 is selected from the group consisting of methyl, ethyl,dimethyl, spirocyclopropyl, methoxy, 2-thienyl and 2-furyl.
 11. Acompound having the following formula:

wherein: (a) X is selected from the group consisting of

(b)R1 is selected from the group consisting of C₃ to about C₅cycloalkyl, C₁ to about C₂ alkanyl, C₂ to about C₃ linear alkenyl, C₃ toabout C₄ branched alkanyl or alkenyl, all such alkyl or cycloalkylmoieties being unsubstituted or substituted with from 1 to about 3fluoro; and phenyl, unsubstituted or substituted with from 1 to about 3fluoro, or with one hydroxy in the 4-position; (c) R3 is hydrogen orhydroxy; (d) R5 is selected from the group consisting of hydrogen,hydroxy, amino, halo, C₁ to about C₂ alkanyl, C₂ alkenyl, and methoxy,all such alkyl and methoxy moieties being unsubstituted or substitutedwith from 1 to about 3 fluoro; (e) R6 is hydroxy; (f) R8 is methoxy ormethylthio, unsubstituted or substituted with from 1 to about 3 fluoro;(g) R7 is amino which is attached to a ring carbon of X which is notadjacent to the ring nitrogen, the amino being unsubstituted orsubstituted with one or two C₁ to about C₃ alkanyl; or aminoalkanylwhich is attached to any ring carbon of X and is C₁ to about C₃ alkanylsubstituted with one amino, the amino being unsubstituted or substitutedwith one or two C₁ to about C₃ alkanyl; (h) each R9 is independentlyselected from the group consisting of hydrogen, C₁ to about C₄ alkanyl,C₂ to about C₆ alkenyl or alkynyl, and a C₃ to about C₆ fused orspirocycle alkyl ring; or one R9 may optionally be selected from thegroup consisting of hydroxy, C₁ to about C₄ alkoxy, aryl and heteroaryl,all other R9 being hydrogen; all alkyl and aryl portions of R9 moietiesbeing unsubstituted or substituted with one hydroxy or with from 1 toabout 3 fluoro; and (j) a R7 moiety described in (g) and a R9 moietydescribed in (h) may optionally be connected thus forming a fused orspirocycle ring with the N-containing ring shown in (a), the fused orspirocycle ring comprising from 2 to about 5 ring carbons and 0 or 1ring nitrogen; an optical isomer, diastereomer or enantiomer thereof; apharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester,amide or imide thereof.
 12. The compound of claim 11 wherein: (a) X is

(b) R1 is selected from the group consisting of C₃ to C₅ cycloalkanyl,methyl, ethyl, ethenyl, isopropyl, isopropenyl, isobutyl, isobutenyl,t-butyl, all such alkyl or cycloalkanyl moieties being unsubstituted orsubstituted with from 1 to 3 fluoro; and phenyl, unsubstituted orsubstituted with from 1 to 3 fluoro, or with one hydroxy in the4-position; (c) R3 is hydroxy; (d) R5 is selected from the groupconsisting of hydrogen, hydroxy, amino, fluoro, chloro, bromo, andmethyl, the methyl being unsubstituted or substituted with from 1 to 3fluoro; (e) R7 is attached to a ring carbon of X which is not adjacentto the ring nitrogen; and (f) no more than two ring carbons of X havenon-hydrogen R9's attached thereto.
 13. The compound of claim 12wherein: (a) R1 is selected from the group consisting of cyclopropyl,ethyl, phenyl substituted with 1 to 3 fluoro, and 4-hydroxyphenyl; (b)R5 is selected from the group consisting of hydrogen, hydroxy, chloro,bromo, amino, and methyl, the methyl being unsubstituted or substitutedwith from 1 to 3 fluoro; (c) R8 is methoxy, unsubstituted or substitutedwith from 1 to 3 fluoro; (d) when X comprises the piperidinyl ring, R7is amino unsubstituted or substituted with one C₁ to C₃ alkanyl or twomethyl; when X comprises the pyrrolidinyl ring, R7 is aminoalkanyl whichis methyl or ethyl or isopropyl substituted with one amino unsubstitutedor substituted with one methyl or ethyl or dimethyl.
 14. The compound ofclaim 13 wherein: (a) R1 is cyclopropyl or ethyl, unsubstituted orsubstituted with from 1 to about 3 fluoro; (b) R5 is selected from thegroup consisting of hydrogen, hydroxy, amino, and methyl; (c) R8 isunsubstituted methoxy; (d) when X comprises the piperidinyl ring, R7 isamino or methylamino in the 3-position or 4-position of the ring; when Xcomprises the pyrrolidinyl ring, R7 is selected from the groupconsisting of aminomethyl, methylaminomethyl, 1-aminoethyl,1-methylaminoethyl, 1-amino-1-methylethyl and 1-methyamino-1-methylethylin the 3-position of the ring; (e) all R9 are hydrogen or only one ringcarbon of X has a non-hydrogen R9 attached thereto, Such non-hydrogen R9being selected from the group consisting of methyl, ethyl, dimethyl andspirocyclopropyl.
 15. A compound having the following formula:

wherein: (a) X is selected from the group consisting of

(b) R1 is selected from the group consisting of C₃ to about C₅cycloalkyl, C₁ to about C₂ alkanyl, C₂ to about C₃ linear alkenyl, C₃ toabout C₄ branched alkanyl or alkenyl, all such alkyl or cycloalkylmoieties being unsubstituted or substituted with from 1 to about 3fluoro; and phenyl, unsubstituted or substituted with from 1 to about 3fluoro, or with one hydroxy in the 4-position; (c) R3 is hydrogen orhydroxy; (d) R5 is selected from the group consisting of hydrogen,hydroxy, amino, halo, C₁ to about C₂ alkanyl, C₂ alkenyl, and methoxy,all such alkyl and methoxy moieties being unsubstituted or substitutedwith from 1 to about 3 fluoro; (e) R6 is selected from the groupconsisting of C₁ to about C₂ alkanyl, C₂ to about C₄ alkenyl or alkynyl,all such alkyl moieties being unsubstituted or substituted with from 1to about 3 fluoro, or such methyl or ethyl moieties being optionallysubstituted with one hydroxy or amino; (f) R8 is methoxy or methylthio,unsubstituted or substituted with from 1 to about 3 fluoro; (g) R7 isamino which is attached to a ring carbon of X which is not adjacent tothe ring nitrogen, the amino being unsubstituted or substituted with oneor two C₁ to about C₃ alkanyl; or aminoalkanyl which is attached to anyring carbon of X and is C₁ to about C₃ alkanyl substituted with oneamino, the amino being unsubstituted or substituted with one or two C₁to about C₃ alkanyl; (h) each R9 is independently selected from thegroup consisting of hydrogen, C₁ to about C₄ alkanyl, C₂ to about C₆alkenyl or alkynyl, and a C₃ to about C₆ fused or spirocycle alkyl ring;or one R9 may optionally be selected from the group consisting ofhydroxy, C₁ to about C₄ alkoxy, aryl and heteroaryl, all other R9 beinghydrogen; all alkyl and aryl portions of R9 moieties being unsubstitutedor substituted with one hydroxy or with from 1 to about 3 fluoro; and aR7 moiety described in (g) and a R9 moiety described in (h) mayoptionally be connected thus forming a fused or spirocycle ring with theN-containing ring shown in (a), the fused or spirocycle ring comprisingfrom 2 to about 5 ring carbons and 0 or 1 ring nitrogen; an opticalisomer, diastereomer or enantiomer thereof; apharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester,amide or imide thereof.
 16. The compound of claim 15 wherein: (a) X is

(b) R1 is selected from the group consisting of C₃ to C₅ cycloalkanyl,methyl, ethyl, ethenyl, isopropyl, isopropenyl, isobutyl, isobutenyl,t-butyl, all such alkyl or cycloalkanyl moieties being unsubstituted orsubstituted with from 1 to 3 fluoro; and phenyl, unsubstituted orsubstituted with from 1 to 3 fluoro, or with one hydroxy in the4-position; (c) R3 is hydroxy; (d) R5 is selected from the groupconsisting of hydrogen, hydroxy, amino, fluoro, chloro, bromo, andmethyl, the methyl being unsubstituted or substituted with from 1 to 3fluoro; (e) R6 is methyl or ethenyl, the ethenyl being unsubstituted orsubstituted with from 1 to 3 fluoro, the methyl being unsubstituted orsubstituted with one hydroxy or amino or from 1 to 3 fluoro; (f) R7 isattached to a ring carbon of X which is not adjacent to the ringnitrogen; and (g) no more than two ring carbons of X have non-hydrogenR9's attached thereto.
 17. The compound of claim 16 wherein: (a) R1 isselected from the group consisting of cyclopropyl, ethyl, phenylsubstituted with 1 to 3 fluoro, and 4-hydroxyphenyl; (b) R5 is selectedfrom the group consisting of hydrogen, hydroxy, chloro, bromo, amino,and methyl, the methyl being unsubstituted or substituted with from 1 to3 fluoro; (c) R6 is methyl, unsubstituted or substituted with from 1 to3 fluoro; (d) R8 is methoxy, unsubstituted or substituted with 1 to 3fluoro; (e) when X comprises the piperidinyl ring, R7 is aminounsubstituted or substituted with one C₁ to C₃ alkanyl or two methyl;when X comprises the pyrrolidinyl ring, R7 is aminoalkanyl which ismethyl or ethyl or isopropyl substituted with one amino unsubstituted orsubstituted with one methyl or ethyl or dimethyl.
 18. The compound ofclaim 17 wherein: (a) R1 is cyclopropyl or ethyl, unsubstituted orsubstituted with from 1 to about 3 fluoro; (b) R5 is selected from thegroup consisting of hydrogen, hydroxy, amino, and methyl; (c) R8 isunsubstituted methoxy; (d) when X comprises the piperidinyl ring, R7 isamino or methylamino in the 3-position or 4-position of the ring; when Xcomprises the pyrrolidinyl ring, R7 is selected from the groupconsisting of aminomethyl, methylaminomethyl, 1-aminoethyl,1-methylaminoethyl, 1-amino-1-methylethyl and 1-methyamino-1-methylethyl in the 3-position of the ring; (e) all R9 are hydrogen or only onering carbon of X has a non-hydrogen R9 attached thereto, suchnon-hydrogen R9 being selected from the group consisting of methyl,ethyl, dimethyl and spirocyclopropyl.
 19. A compound selected from thegroup consisting of:7-[3R-(1S-aminoethylpyrrolidinyl)]-1-ethyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1S-aminoethylpyrrolidinyl)-1-(2-fluoroethyl)]-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1S-aminoethylpyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1S-methylaminoethylpyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1-amino-methylethylpyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1-methylamino-methylethylpyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1S-aminoethyl-5-methyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1S-aminoethyl-5,5-dimethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1-aminomethylethyl-5,5-dimethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1S-methylaminoethyl-5,5-dimethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1-methylaminomethylethyl-5,5-dimethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1S-aminoethyl-5-ethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1-aminomethylethyl-5-ethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1S-methylaminoethyl-5-ethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1-methylaminomethylethyl-5-ethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3R-(1-amino-1-cyclopropyl-methylpyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[6R-(1S-aminoethyl)-4-azaspiro[2.4]heptanyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[6R-(1S-methylaminoethyl)-4-azaspiro[2.4]heptanyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[6R-(1S-amino-methylethyl)-4-azaspiro[2.4]heptanyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[6R-(1S-methylamino-methylethyl)-4-azaspiro[2.4]heptanyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid; or a pharmaceutically-acceptable salt thereof.
 20. A compoundselected from the group consisting of:7-[3S-aminopiperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3S-methylaminopiperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3S-amino-4R-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3S-amino-5S-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3S-amino-5R-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3S-amino-4R-ethyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3S-amino-6,6-dimethyl-piperidinyl]-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[3S-amino-6-methyl-piperidinyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[7-amino-5-azaspiro[2.5]-octanyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid;7-[4-amino-6-azaspiro[2.5]-octanyl]-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid; or a pharmaceutically-acceptable salt thereof.
 21. The compound ofclaim 3 wherein each R9 is independently selected from the groupconsisting of hydrogen, C₁ to about C₄ alkanyl, C₂ to about C₆ alkenylor alkynyl, and a C₃ to about C₆ fused or spirocycle alkyl ring; allsuch alkyl moieties being unsubstituted or substituted with from 1 toabout 3 fluoro.
 22. The compound of claim 11 wherein each R9 isindependently selected from the group consisting of hydrogen, C₁ toabout C₄ alkanyl, C₂ to about C₆ alkenyl or alkynyl, and a C₃ to aboutC₆ fused or spirocycle alkyl ring; all such alkyl moieties beingunsubstituted or substituted with from 1 to about 3 fluoro.
 23. Thecompound of claim 15 wherein each R9 is independently selected from thegroup consisting of hydrogen, C₁ to about C₄ alkanyl, C₂ to about C₆alkenyl or alkynyl, and a C₃ to about C₆ fused or spirocycle alkyl ring;all such alkyl moieties being unsubstituted or substituted with from 1to about 3 fluoro.
 24. The compound of claim 4 wherein: (a) R7 is aminowhich is attached to a ring carbon of X which is not adjacent to thering N, the amino being unsubstituted or substituted with one or two C₁to about C₃ alkanyl; or is C₁ to about C₃ alkanyl substituted with oneamino; and (b) R9 is selected from the group consisting of hydrogen, C₁to about C₄ alkanyl, C₂ to about C₆ alkenyl or alkynyl, and a C₃ toabout C₆ spirocycle alkyl ring; all such alkyl moieties beingunsubstituted or substituted with from 1 to about 3 fluoro.
 25. Thecompound of claim 12 wherein: (a) R7 is amino which is attached to aring carbon of X which is not adjacent to the ring N, the amino beingunsubstituted or substituted with one or two C₁ to about C₃ alkanyl; oris C₁ to about C₃ alkanyl substituted with one amino; and (b) R9 isselected from the group consisting of hydrogen, C₁ to about C₄ alkanyl,C₂ to about C₆ alkenyl or alkynyl, and a C₃ to about C₆ spirocycle alkylring; all such alkyl moieties being unsubstituted or substituted withfrom 1 to about 3 fluoro.
 26. The compound of claim 16 wherein: (a) R7is amino which is attached to a ring carbon of X which is not adjacentto the ring N, the amino being unsubstituted or substituted with one ortwo C₁ to about C₃ alkanyl; or is C₁ to about C₃ alkanyl substitutedwith one amino; and (b) R9 is selected from the group consisting ofhydrogen, C₁ to about C₄ alkanyl, C₂ to about C₆ alkenyl or alkynyl, anda C₃ to about C₆ spirocycle alkyl ring; all such alkyl moieties beingunsubstituted or substituted with from 1 to about 3 fluoro.
 27. Thecompound ethyl 2,4-difluoro-3-methoxy-benzoyl acetate.
 28. The compoundethyl 3-cyclopropylamino-2-(2,4-difluoro-3-methoxy-benzoyl) acrylate.29. The compound ethyl1-cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylate.30. The compound1-cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylicacid.
 31. The compound1-cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylicacid boron difluoride complex.
 32. A compound having the followingformula:

wherein: (a) X is selected from the group consisting of

(b) R1 is selected from the group consisting of C₃ to about C₅cycloalkyl, C₁ to about C₂ alkanyl, C₂ to about C₃ linear alkenyl, C₃ toabout C₄ branched alkanyl or alkenyl, all such alkyl or cycloalkylmoieties being unsubstituted or substituted with from 1 to about 3fluoro; and phenyl, unsubstituted or substituted with from 1 to about 3fluoro, or with one hydroxy in the 4-position; (c) R3 is hydrogen orhydroxy; (d) R5 is selected from the group consisting of hydrogen,hydroxy, amino, halo, C₁ to about C₂ alkanyl, C₂ alkenyl, and methoxy,all such alkyl and methoxy moieties being unsubstituted or substitutedwith from 1 to about 3 fluoro; (e) R6 is selected from the groupconsisting of hydrogen, hydroxy, aminocarbonyl, bromo, cyano, C₁ toabout C₂ alkanyl, C₂ to about C₄ alkenyl or alkynyl, all such alkylmoieties being unsubstituted or substituted with from 1 to about 3fluoro, or such methyl or ethyl moieties being optionally substitutedwith one hydroxy or amino; (f) R8 is methoxy, methylthio, or C₁ to aboutC₃ alkanyl, unsubstituted or substituted with from 1 to about 3 fluoro;(g) R7 is amino which is attached to a ring carbon of X which is notadjacent to the ring nitrogen, the amino being unsubstituted orsubstituted with one or two C₁ to about C₃ alkanyl; or aminoalkanylwhich is attached to any ring carbon of X and is C₁ to about C₃ alkanylsubstituted with one amino, the amino being unsubstituted or substitutedwith one or two C₁ to about C₃ alkanyl; (h) each R9 is independentlyselected from the group consisting of hydrogen, C₁ to about C₄ alkanyl,C₂ to about C₆ alkenyl or alkynyl, and a C₃ to about C₆ fused orspirocycle alkyl ring; or one R9 may optionally be selected from thegroup consisting of hydroxy, C₁ to about C₄ alkoxy, aryl and heteroaryl,all other R9 being hydrogen; all alkyl and aryl portions of R9 moietiesbeing unsubstituted or substituted with one hydroxy or with from 1 toabout 3 fluoro; and (j) a R7 moiety described in (g) and a R9 moietydescribed in (h) may optionally be connected thus forming a fused orspirocycle ring with the N-containing ring shown in (a), the fused orspirocycle ring comprising from 2 to about 5 ring carbons and 0 or 1ring nitrogen; an optical isomer, diastereomer or enantiomer thereof; apharmaceutically-acceptable salt, hydrate, or biohydrolyzable ester,amide or imide thereof.
 33. A pharmaceutical composition comprising: (a)a safe and effective amount of a compound of any one of claims 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 12, 16, 19, 20 or 32; and (b) apharmaceutically-acceptable excipient.
 34. A method for preventing ortreating microbial infection comprising administering to a host in needof such a treatment a safe and antimicrobially effective amount of acompound of any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 19,20 or
 32. 35. The compound of claim 32 wherein R8 is methoxy ormethylthio, unsubstituted or substituted with from 1 to about 3 fluoro.36. The compound of claim 35 wherein R8 is methoxy, unsubstituted orsubstituted with from 1 to about 3 fluoro.
 37. The compound of claim 1wherein R8 is methoxy or methylthio, unsubstituted or substituted withfrom 1 to about 3 fluoro.
 38. The compound of claim 37 wherein R8 ismethoxy, unsubstituted or substituted with from 1 to about 3 fluoro. 39.A compound having the following formula:

wherein: (a) X is selected from the group consisting of

(b) R1 is selected from the group consisting of C₃ to about C₅cycloalkyl, C₁ to about C₂ alkanyl, C₂ to about C₃ linear alkenyl, C₃ toabout C₄ branched alkanyl or alkenyl, all such alkyl or cycloalkylmoieties being unsubstituted or substituted with from 1 to about 3fluoro; and phenyl, unsubstituted or substituted with from 1 to about 3fluoro, or with one hydroxy in the 4-position; (c) R3 is hydrogen ofhydroxy; (d) R5 is selected from the group consisting of hydrogen,hydroxy, amino, halo, C₁ to about C₂ alkanyl, C₂ alkenyl, and methoxy,all such alkyl and methoxy moieties being unsubstituted or substitutedwith from 1 to about 3 fluoro; (e) R6 is hydroxy; (f) R8 is methoxy,methylthio or C₁ to about C₂ alkanyl, unsubstituted or substituted withfrom 1 to about 3 fluoro; (g) R7 is amino which is attached to a ringcarbon of X which is not adjacent to the ring nitrogen, the amino beingunsubstituted or substituted with one or two C₁ to about C₃ alkanyl; oraminoalkanyl which is attached to any ring carbon of X and is C₁ toabout C₃ alkanyl substituted with one amino, the amino beingunsubstituted or substituted with one or two C₁ to about C₃ alkanyl; (h)each R9 is independently selected from the group consisting of hydrogen,C₁ to about C₄ alkanyl, C₂ to about C₆ alkenyl or alkynyl, and a C₃ toabout C₆ fused or spirocycle alkyl ring; or one R9 may optionally beselected from the group consisting of hydroxy, C₁ to about C₄ alkoxy,aryl and heteroaryl, all other R9 being hydrogen; all alkyl and arylportions of R9 moieties being unsubstituted or substituted with onehydroxy or with from 1 to about 3 fluoro; and (j) a R7 moiety describedin (g) and a R9 moiety described in (h) may optionally be connected thusforming a fused or spirocycle ring with the N-containing ring shown in(a), the fused or spirocycle ring comprising from 2 to about 5 ringcarbons and 0 or 1 ring nitrogen; an optical isomer, diastereomer orenantiomer thereof; a pharmaceutically-acceptable salt, hydrate, orbiohydrolyzable ester, amide or imide thereof.
 40. The compound of claim39 wherein R3 is hydroxy, and X is


41. The compound of claim 40 wherein R8 is methoxy or methylthio,unsubstituted or substituted with from 1 to about 3 fluoro.
 42. Thecompound of claim 41 wherein R8 is methoxy, unsubstituted or substitutedwith from 1 to about 3 fluoro.
 43. The compound of claim 40 wherein eachR9 is independently selected from the group consisting of hydrogen, C₁to about C₄ alkanyl, C₂ to about C₆ alkenyl or alkynyl, and a C₃ toabout C₆ fused or spirocycle alkyl ring; all such alkyl moieties beingunsubstituted or substituted with from 1 to about 3 fluro.
 44. Thecompound of claim 43 wherein: (a) R1 is selected from the groupconsisting of C₃ to C₅ cycloalkanyl, methyl, ethyl, ethenyl, isopropyl,isopropenyl, isobutyl, isobutenyl, t-butyl, all such alkyl orcycloalkanyl moieties being unsubstituted or substituted with from 1 to3 fluoro; and phenyl, unsubstituted or substituted with from 1 to 3fluro, or with one hydroxy in the 4-position; (b) R5 is selected fromthe group consisting of hydrogen, hydroxy, amino, fluoro, chloro, bromo,and methyl, the methyl being unsubstituted or substituted with from 1 to3 fluoro; (c) R8 is methoxy, unsubstituted or substituted with from 1 to3 fluoro. (d) R7 is attached to a ring of carbon of X which is notadjacent to the ring nitrogen; and (e) no more than two ring carbons ofX have non-hydrogen R9's attached thereto.
 45. The compound of claim 44wherein: (a) R7 is amino which is attached to a ring carbon of X whichis not adjacent to the ring N, the amino being unsubstituted orsubstituted with one or two C₁ to about C₃ alkanyl; or is C₁ to about C₃alkanyl substituted with one amino; (b) R9 is selected from the groupconsisting of hydrogen, C₁ to about C₄ alkanyl, C₂ to about C₆ alkenylor alkynyl, and a C₃ to about C₆ spirocycle alkyl ring; all such alkylmoieties being unsubstituted or substituted with from 1 to about 3fluoro.
 46. The compound of claim 44 wherein; (a) R1 is selected fromthe group consisting of cyclopropyl, ethyl, phenyl substituted with 1 to3 fluoro, and 4-hydroxyphenyl; (b) R5 is selected from the groupconsisting of hydrogen, hydroxy, amino, and methyl; (c) R8 isunsubstituted methoxy; (d) X comprises the piperidinyl ring; (e) R7 isamino in the 3-position of the piperidinyl ring; and (f) all R9 arehydrogen, or one non-hydrogen R9 is in the 4-position or 5-position ofthe piperidinyl ring.
 47. The compound of claim 46 wherein: (a) R1 iscyclopropyl, (b) R5 is hydrogen, and (c) all R9 are hydrogen, or onenon-hydrogen R9 is selected from the group consisting of methyl, ethyl,dimethyl, spirocyclopropyl, methoxy, 2-thienyl and 2-furyl.
 48. Thecompound of claim 44 wherein: (a) R1 is selected from the groupconsisting of cyclopropyl, ethyl, phenyl substituted with 1 to 3 fluoro,and 4-hydroxyphenyl; (b) R5 is selected from the group consisting ofhydrogen, hydroxy, chloro, bromo, amino, and methyl, the methyl beingunsubstituted or substituted with from 1 to 3 fluoro; (c) when Xcomprises the piperidinyl ring, R7 is amino unsubstituted or substitutedwith one C₁ to C₃ alkanyl or two methyl; when X comprises thepyrrolidinyl ring, R7 is aminoalkanyl which is methyl or ethyl orisopropyl substituted with one amino unsubstituted or substituted withone methyl or ethyl or dimethyl.
 49. The compound of claim 48 wherein:(a) R1 is cyclopropyl or ethyl, unsubstituted or substituted with from 1to about 3 fluoro; (b) R5 is selected from the group consisting ofhydrogen, hydroxy, amino, and methyl; (c) R8 is unsubstituted methoxy;(d) when X comprises the piperidinyl ring, R7 is amino or methylamino inthe 3-position or 4-position of the ring; when X comprises thepyrrolidinyl ring, R7 is selected from the group consisting ofaminomethyl, methylaminomethyl, 1- aminoethyl, 1-methylaminoethyl,1-amino-1-methylethyl and 1-methylamino-1- methylethyl in the 3-positionof the ring. (e) all R9 are hydrogen or only one ring carbon of X has anon-hydrogen R9 attached thereto, such non-hydrogen R9 being selectedfrom the group consisting of methyl, ethyl, dimethyl andspirocyclopropyl.
 50. The compound of claim 49 wherein X comprises thepyrrolidinyl ring.
 51. The compound of claim 50 wherein R1 iscyclopropyl, R5 is hydrogen, and all R9 are hydrogen.
 52. Apharmaceutical composition comprising: (a) a safe and effective amountof a compound of claim 39; and (b) a pharmaceutically-acceptableexcipient.
 53. A method for preventing or treating microbial infectioncomprising administering to a host in need of such a treatment a safeand antimicrobially effective amount of a compound of claim 39.